Impact of Host Genetics on Susceptibility and Resistance to Mycobacterium avium Subspecies Paratuberculosis Infection in Domestic Ruminants
Shoor Vir Singh,
Kundan Kumar Chaubey,
Pravin Kumar Singh,
Jagdip Singh Sohal,
Ajay Vir Singh,
Amit Kumar Verma,
Johnes disease or Paratuberculosis has emerged as major infectious disease of animals in general and domestic livestock in particular on global basis. There have been major initiatives in developed countries for the control of this incurable malady of animals and human beings alike (inflammatory bowel disease or Crohns disease). Disease has not received similar attention due to inherent complexities of disease, diagnosis and control, in resource poor counties around the world. However, the rich genetic diverstiy of the otherwise low productive animal population offers opportunity for the control of Johnes disease and improve per animal productivity. Present review aims to gather and compile information available on genetics or resistance to Johnes disease and its future exploitation by resource poor countries rich in animal diversity. This review will also help to create awareness and share knowledge and experience on prevalence and opportunities for control of Johnes disease in the livestock population to boost per animal productivity among developing and poor countries of the world. Breeding of animals for disease resistance provides good, safe, effective and cheaper way of controlling Johnes disease in animals, with especial reference to domestic livestock of developing and poor countries. Study will help to establish better understanding of the correlation between host cell factors and resistance to MAP infection which may have ultimately help in the control of Johnes disease in future.
to cite this article:
Shoor Vir Singh, Kuldeep Dhama, Kundan Kumar Chaubey, Naveen Kumar, Pravin Kumar Singh, Jagdip Singh Sohal, Saurabh Gupta, Ajay Vir Singh, Amit Kumar Verma, Ruchi Tiwari, Mahima , S. Chakraborty and Rajib Deb, 2013. Impact of Host Genetics on Susceptibility and Resistance to Mycobacterium avium Subspecies Paratuberculosis Infection in Domestic Ruminants. Pakistan Journal of Biological Sciences, 16: 251-266.
Received: November 03, 2012;
Accepted: February 14, 2013;
Published: March 21, 2013
Mycobacteria are either saprophytic or obligatory ancient microbes (Hett
and Rubin, 2008; Ventura et al., 2007; Deb
and Goswami, 2010) causing infection in even camel (Ghosh
et al., 2012). Mycobacterium avium subspecies paratuberculosis
(MAP) is the etiological agent of Johnes disease (Verschoor
et al., 2010b; Momotani, 2012; Dobson
et al., 2013). It is a deadly intestinal ailment leading to chronic
enteritis as well as granulomatous inflammation of lymph nodes in ruminants
(Pant et al., 2011; Deb and
Goswami, 2011). Disease adversely affects productivity and viability of
animal industry across the world by causing significant economic losses by way
of reduced productivity, premature culling and mortality (Pant
et al., 2010, 2011). Paratuberculosis has
been characterized as the most costly infectious disease of dairy cattle. Recent
evidences on the potential role of MAP in causation of Inflammatory Bowels
Disease (IBD) or, Crohns Disease (CD) in human beings (Hermon-Taylor,
2009; Greenstein, 2003). Collins
(2011) and Sweeney et al. (2012) have further
underlined the importance of controlling MAP infection both in animal and human
population world-wide. Therefore, concerted global efforts are required on priority
to restrict the spread of MAP infection both in animals and human beings in
order to boost per animal productivity and safeguard human health globally.
Control methods so far employed viz., hygienic management practices, test and
cull policy and vaccination measures have either failed or did not yield desired
results. Therefore, the role of host genetics is an alternative approach which
has recently been studied by many leading workers in order to control chronic
diseases like Johnes disease (Pant et al.,
2010; Kirkpatrick and Shook, 2011). In fact, development
of genetically resistant animals through selective breeding for disease resistant
traits in the host species is a slow and long term process but its impact are
stable and the genetic resistance gained in one generation is likely to remain
its next counterpart. Therefore, host genetics and breeding of animals for disease
resistant traits may be an alternative and effective approach in reducing prevalence
of MAP infection in the domestic ruminants. Selective breeding programme will
help in establishment of genetically resistant animals in a population thereby
improving the herd immunity. This review focus to establish better
understanding of the correlation between host cell factors and natural resistance
to MAP infection which may have significant impact in controlling Johnes
disease specially in the resource poor countries of the world with enough genetic
Breed differences play major role on the genetics of disease resistance (Lindhe
and Philipsson, 1998; Raadsma et al., 1998)
and can be used as tool for the control of disease (Van
Hulzen et al., 2011). Breed effects with respect to MAP infection
have also been experienced and studied in the population of domestic ruminants
in India (Singh et al.,2012a, b;
Singh et al., 2009) reported better adaptation
of Indian Bison Type biotype of MAP in different breeds of farm
goats of Uttar Pradesh as compared to farm goats in Rajasthan. Local breeds
are resistant to these diseases in tropical regions compared to imported breeds
imported breeds (Savic et al., 1995) and their
crosses. Major role of environment with respect to breeds located in different
agro climatic zones cannot be ruled out and it has tremendous impact on evolution
or survival of these breeds over the years. Besides physical environment (arid
or semi arid, more sunshine, dry conditions etc.), it is the animal profiles
(colour of skin and hairs), livestock husbandry practices, management (stocking
density, intensive or extensive or migratory system of management),) etc., play
important role on the prevalence of disease in particular agro-climatic region.
Channel Island and Shorthorn cattle showed a particularly high incidence of
Johnes disease (Withers, 1959) while exotic sheep
breeds viz., Scottish Black face, Shetland; cattle viz: Limousin, Channel Island
breeds (Jersey and Guernesy) are prone to disease (Clarke,
1997). (Manning and Collins, 2001; Collins
et al., 2001). In UK a number of cattle breeds have a reputation
for susceptibility to JD. Merino as well as some dairy breeds of sheep may be
more susceptible to MAP infection than other breeds, however the genetic resistance
to JD has not been identified yet. Variation in genetic susceptibility of breeds
have also been observed with respect to different blood lines (Koets
et al., 2000), therefore careful selection and description of animals
will be important for the eventual disease outcome with respect to disease and
reproducibility of the trials.
SKIN OR COAT COLOUR
Skin or coat colour has impact on the genetic resistance against various diseases.
Different skin and coat colours in different breeds of domestic animals have
emerged as part of natures strategy for survival and mitigate heat stress
and diseases in various climatic conditions. Melanin is the main participants
in colour based resistance or susceptibility to environment and disease. Melanin
has several physiological roles in maintaining health viz. synthesis of vitamin
D which works as a modulator of the different processes of the immune system,
skin pigmentation and thermo-regulation and protect the body from harmful ultraviolet
radiation. Autoimmune diseases in certain breeds is influenced by latitude (Shoenfeld
et al., 2009). Genes for melanism in felines may provide resistance
to viral infections. In Java and Malaysia, there is high prevalence of black
leopards and black servals, the reason might be the high altitude adaptation
since black fur absorbs more heat (Seidensticker and Lumpkin,
2006). Later on, the study published in New Scientist magazine in 2003 suggested
that recessive-gene melanism is linked to disease resistance instead of altitude.
Resistance power is higher in Melanistic cats compared to cats having normal
coat colour. Similar advantage of dark colour goat breeds and sheep with wool
coat have been experienced by the author in last 29 years of experience in working
with different breeds of goats and sheep with respect to Johnes disease.
Disease is endemic in farm herds of goats and sheep at CIRG, Makhdoom, where
dark colour breeds (Jakhrana, Marwari and Sirohi) have shown better adaptability
to MAP infection (Singh et al., 2009). Though
the role of other factors like duration of existence of breeds at the farm,
since breeds from Rajasthan were introduced in 1990s as compared to Barbari
and Jamunapari breeds of goats which are maintained since 1976, The better performance
of the only sheep breed (Muzaffarinagri) located at CIRG, Makhdoom, is due to
fast development of rumen, better capacity of sheep to drive nutritional requirement
from poor quality and deficient grazing resources. Sheep graze as compared to
goat which browses and needs good plantation which is not available as these
farm exists on the wastelands of river Yamuna on CIRG campus. Earlier in sheep
unit there existed crosses of Suffock and Dorset with native Muzaffarnagri breed
and suffered from different kinds of health problems, were therefore removed
in favour of pure Muzaffarnagri breed. Lastly the goat adapted MAP strain may
be acting as vaccine strain for minority species, i.e., sheep. Similarly
better performance of Sirohi goats in the Central Sheep and Wool Research Institute
is due to adaptation of MAP strain to sheep and vaccine strain for
goats the minority species. In this interplay of events, availability of energy
resources is critical and is directly affected by skin and coat colour especially
in winter climate.
Each living creature on earth is also affected by its physical non-living (abiotic)
and biotic environment and innate potential viz., reproductive and growth rate,
ability to migrate and invade new habitats, ability to cope with adverse conditions,
defence mechanisms. Factors responsible for development of environmental resistance
are adverse conditions viz., insufficient nutrients and water, unsuitable habitat,
adverse weather, predators, disease and competition. Malnutrition generally
alters resistance of the host to infection and infectious disease exaggerates
existing malnutrition (WHO monographs series 57). There is increasing reports
that slow and mild exposure to some environmental pollutants may disturb immune
responsiveness and change the susceptibility of animals to pathogens (Bradley
and Morahan, 1982). Authors have experienced the role of nutrition in immune
response to vaccination against Johnes disease and observed dramatic results
in intensively fed goats/sheep/cattle as compared to poorly fed animals where
vaccine response was slow in endemically infected herds and flocks.
Study of host genetics for the identification of host genes involved in susceptibility
and resistance to infectious diseases uses diverse designs including animal
models, observation of individuals with marked susceptibility or resistance,
study of candidate genes for common infections, race or family-based, genome-wide,
linkage studies etc. Genome-wide linkage studies enable the identification of
regions containing major disease-susceptibility loci (Pant
et al., 2010; Deb et al., 2012). This
approach is very systematic and comprehensive but has very low power. It will
therefore not detect genes which exert a moderate effect on population-wide
disease risks. Association-based, candidate gene studies have comparatively
much greater power. A case-control study of candidate gene approach, when used
alone; it failed to detect the gene exerting the largest population effects
on disease susceptibility. Identification of the genes responsible for susceptibility
to atypical mycobacterial infections provides valuable insight into the host
immune response. The identified molecular marker through candidate gene studies
and whole genome association studies for resistance to Johnes disease
will help in enhancing the overall herd resistance by encouraging
the selective breeding of resistant animals. Similarly, genetic variations that
exits in the population of domestic animals in terms of breeds and strains emerged
in particular agro-climatic regions contribute to host susceptibility to MAP
infection are also very important to uniform animal improvement programmes aimed
at reducing susceptibility to infection and for gaining a better understanding
of the mechanisms of disease. Overall, the study may aid in designing the more
efficacious and safer strategies for the control and eradication of Johnes
disease from endemically infected herds/flocks.
HOST RESPONSE AGAINST PARATUBERCULOSIS
Survivality of Mycobacteria is similar to other Mycobacteria. One feature of
mycobacteria, including MAP, is their propensity to infect macrophages. Within
macrophages MAP interferes with the maturation of the phagosome by unknown mechanisms,
thereby evading the host's normal first line of defence against bacterial pathogens.
Moreover, MAP has been shown to decrease MHC expression by macrophages (Weiss
et al., 2008). Due to impaired innate responses local macrophages
will be unable to destroy the phagocytosed MAP and significant bacterial multiplication
within macrophages occurs. The host immune system starts a series of attacks
against MAP infected macrophages, including the rapid deployment of gamma delta
T cells, CD4+T cells and cytolytic CD8+T cells (Charavaryamath
et al., 2013). Macrophages may be lysed (by the direct effects of
bacteria or by cytotoxic cells) and release bacteria, or infected macrophages
may themselves divide. The acid fast organism invades sheep macrophages (Rajya
and Singh, 1961). Alonso-Hearn et al. (2008)
reported that, MAP3464 gene of M. avium subsp. Paratuberculosis which codes
for Oxidoreductase are linked with activation Cdc42 in the host cell.
Blood borne monocyte (immature macrophages) are attracted by cytokines released
by infected macrophages or by bacterial products and ingest any released bacteria.
By this stage sufficient antigens may be present for the initiation of specific
immune responses and sufficient organisms may be present for detection of infection
by culture of intestinal tissues. It is highly likely that even at this early
stage migration of infected macrophages to the regional MLN occurs. The subsequent
development of specific immunity might lead to complete elimination or restriction
of infection due to strong Th1 responses (with the possibility of later exacerbation),
or progression of the disease to the terminal stages due to shift from protective
Th1 to non-protective Th2 responses. It is very clear that misdirected immune
response due to MAP related host modulation leads to establishment of this debilitating
disease. Inhibition of phagosomal maturation, reduction in apoptosis of infected
cells, reduced MHC II expression, Th1-Th2 shift and increase of suppressive
population of gamma delta (γδ) T cells, inhibition of CD4+ T cell
activity, inhibition of TLR9 mediated response, inhibition of gamma interferon
induced signalling in monocytes and immune anergy are the seminal events that
develops persistency of MAP infection (Sohal et al.,
2008; Begg et al., 2011; Dobson
et al., 2013; Charavaryamath et al.,
2013; Arsenault et al., 2012, 2013).
EVIDENCE THAT GENETIC FACTORS INFLUENCE RESISTANCE TO PARATUBERCULOSIS
It has been hypothesized that during the interaction between host immunity
and MAP, a deviation from the proper immune response arises and disrupts the
ability of the host to contain the disease. Without doubt, present disease control
measures had helped to some extent but are not strong enough to yield desired
results and paratuberculosis still continues to be a problem for animal industry
world over. Therefore an alternative approach to this problem is genetics of
disease resistance which is the inherent capacity of an animal to
resist disease when challenged by the pathogen. Recent studies identified host
cell factors MHC, NOD 2/CARD 15, (BoLA) DRB3, IFN γ, TLR, SLC11A1, (solute
carrier family 11 member 1) formerly known as NRAMP 1, IL10RA, SP110/Ipr1, PGRP,
ANKRA2, CD180 so on., responsible for resistance/susceptibility to MAP infection
(Koets et al., 2000; Mortensen
et al., 2004; Reddacliff et al., 2005;
Gonda et al., 2006; Pinedo
et al., 2009a, b; Singh
et al., 2009, 2012a, b;
Ruiz-Larranaga et al., 2010; Pant
et al., 2011; Casas et al., 2011;
Rastislav and Mangesh, 2012). Recently, various studies
on genome wide profiling of paratuberculosis infection has also emerged (Minozzi
et al., 2010).
CANDIDATE GENE STUDIES
Genetic factors have long been suspected in association with susceptibility
and resistance to mycobacterial infection including bovine paratuberculosis
(Abel and Casanova, 2000; Koets
et al., 2000; Purdie et al., 2011;
Deb et al., 2012). Several studies reported a
breed effect in the variation in susceptibility to paratuberculosis (Cetinkaya
et al., 1997; Roussel et al., 2005;
Elzo et al., 2006; Singh
et al., 2009; Ruiz-Larranaga et al.,
2010; Purdie et al., 2011; Rastislav
and Mangesh, 2012) and estimations of heritability to MAP infection ranging
from 0.041-0.159 have been reported (Koets et al.,
2000; Mortensen et al., 2004; Gonda
et al., 2006; Van Hulzen et al., 2011).
MHC CLASS OF GENES
In recent years, research on the Major Histocompatibility Complex (MHC) as
candidate genes of disease associations has been initiated (Purdie
et al., 2011). MHC (genes closely clustered) binds with processed
antigen thereby presenting to T cells, thus playing role in immunological functions
apart from the non-immunological ones (Deb and Goswami, 2011).
MHC class I molecules are present on the membrane of all nucleated cells and
present antigens to cytotoxic T cells. MHC class II is mainly located on the
cells of the immune system and present antigens to helper T cells. Depending
on the antigen or, epitope presented these responses could led to protective
immunity to DTH ()or, to immune suppression (De Vries,
1991). Located between the Class I and Class II gene (in humans at least)
are genes for complement factors and TNF all of which are potentially important
in immune function.
Genetic associations between the MHC and susceptibility to certain infectious
diseases like tuberculosis, leprosy etc., have been identified in human beings
(Goldfeld et al., 1998; Ravikumar
et al., 1999). Studies have demonstrated that caprine MHC I and II
genes are highly polymorphic (Cameron et al., 1990)
in which DRB regions are most polymorphic (Andersson and
Rask, 1988) as well as play major role in disease resistance (Longenecker
and Gallatin, 1978; Schierman and Collins, 1987;
Kaufman and Venugopal, 1998; Reddacliff
et al., 2005; Sayers et al., 2005;
Li et al., 2010). Two Single Nucleotide Polymorphisms
(SNPs) in the DRB region (detected by PCR-RFLP method using PstI and TaqI restriction
endonuclease) were described by Amills et al. (1995),
leading to amino acid substitutions in the antigen binding site of the caprine
MHC molecules. Bovine Leucocyte Antigen (BoLA) is a part of the Major Histocompatibility
Complex (MHC) of cattle. The BoLA-DRB3 gene, one of the MHC II groups of genes,
plays a key role in the immune response by presenting peptides derived from
extracellular proteins. A single nucleotide polymorphism at the antigen recognition
site of the Bovine Leucocyte Antigen (BoLA) DRB3 gene was studied in healthy
and MAP infected cattle. Four mutations, Val53Glu (OR 453.7), VAL53Leu (OR 453.7),
Asp57His (OR 1.944) and Arg84Gly (OR 0.453) were linked with high resistance
indicating important mutations in the protein-binding site of DRB3, responsible
for activation of immune response against MAP (Rastislav
and Mangesh, 2012).
In a recent study on 203 Jamunapari goats (Indian vulnerable breed extremely
liable to paratuberculosis), polymorphism was analyzed within the exon-2 of
the caprine MHC Class II DRB region and its association with status (resistance
or susceptibility) to paratuberculosis (Singh et al.,
2012a). On the basis of clinical signs and laboratory examination viz.,
microscopic, faecal culture, ELISA and PCR, sixty and 143 goats were classified
as resistant and liable to paratuberculosis, respectively. PCR-based restriction
fragment length polymorphism (PCR-RFLP) with 2 enzymes (PstI and TaqI) was conjointly
performed to assess variations within the DRB gene(s). The frequency of p and
t alleles of individual pp and tt and of composed pptt genotypes were considerably
higher (Pcorr<0.001) within the resistant group as compared to
the susceptible group, whereas the P and T alleles were related
with susceptibility (Pcorr < 0.001) In heterozygous genotypes, susceptibility
was dominant over the resistance (Singh et al.,
Therefore, investigations of possible relationships between these critical SNPs with resistance or susceptibility to JD are of potential importance. Despite of few evidences indicating the important role of MHC Class II gene in the susceptibility to paratuberculosis, there is a lack of more comprehensive work to further explore the role of this gene in JD occurrence.
NOD2 (CARD15) GENES
The Nucleotide-binding Oligomerization Domain-containing 2 protein gene (NOD2),
previously referred to as the Caspase Recruitment Domain 15 protein gene (CARD15),
is well characterized gene that contributes to predisposition to Crohns
disease in human beings (Hugot, 2006; Purdie
et al., 2011). The product of CARD15 gene is an intracellular element
responsible for the indirect recognition of bacterial peptidoglycan by monocytes,
macrophages, dendritic cells and intestinal epithelial cells (Ogura
et al., 2001a). NOD2 having 5 and 3 flanking and partial
intronic regions is considered as a candidate gene in a wide variety of cattle
based on similarities between Crohns disease and JD (Taylor
et al., 2006). Most of the animals belonging to several different
breeds have shown polymorphism but association of infection with polymorphisms
could not be tested due to study being conducted in small numer of animals Subsequently,
Pinedo et al., 2009a) tested association of
three of the NOD2 polymorphisms identified by Taylor et
al. (2006) in a case-control study in dairy cattle and significant association
haqs been found between two non-synonymous NOD2 SNPs based haplotypes and infection
status that are independent of the breed factor. Future comprehensive investigations
are required to have exhaustive information on the role of this genetic element
in paratuberculosis infection. Based on genetic association, NOD2, has also
found to be a candidate gene for MAP infection in a Bos taurusxBos indicus crossbreds.
Study on Holstein Friesian reported that the C allele of SNP c.*1908C>T,
located in the 3-UTR region of the gene occurred more frequently in infected
animals, indicating the role of bovine NOD2 gene in MAP susceptibility (Ruiz-Larranaga
et al., 2010).
Mutation in a gene ATG16L, NOD2/CARD15, IBD5, CTLA4, TNFSF15 and IL23R genes
are associated with Crohns disease (Ogura et al.,
2001b; Fielding, 1986; Grant
et al., 2008; Gazouli et al., 2010;
Naser et al., 2012), susceptibility being observed
in certain phenotypes mapped to chromosome 16 (Cuthbert
et al., 2002; Hugot et al., 2001).
Three independent studies reported that mutation within the NOD2/CARD15 gene
were strongly linked to Crohns disease in Europeans (Ogura
et al., 2001b; Hugot et al., 2001;
Hampe et al., 2001). Crohnes disease associated
gene without confirmation of association has been reported (Greenstein,
2003), suggesting the tendency of development of the disease in genetically
identifiable sub-populations (Inoue et al., 2002).
Crohns disease in Sardinian population was carried out on several specimens
(few showing no association) based on NOD2/CARD15 gene (insC3020, G908R and
R702W alleles) analysis, indicating 70% susceptibility (Sechi
et al., 2005).
These NOD2 variants Change in the structure of the leucine-rich repeat domain
of the protein occurs due to frame shift variant and two mis-sense variants
of NOD2 encoding a member of the Apaf-1/ Ced-4 superfamily of apoptosis regulators
expressed in monocytes. This NOD2 may also activate another nuclear factor NF-KB
which is regulated by the carboxy-terminal leucine-rich repeat domain. Therefore,
NOD2 gene product is responsible for susceptibility of individuals to Crohns
disease by changing the recognition of these components and/or by over-activating
NF-KB in monocytes (Ogura et al., 2001b).
(BOLA) DRB3 GENE
A single nucleotide polymorphism at the antigen recognition site of the Bovine
Leucocyte Antigen (BoLA) DRB3 gene may also be important for activation of proper
immune response against MAP in cattle (Rastislav and Mangesh,
2012). Mutations like Val53Glu (OR 453.7), Val53Leu (OR 453.7), Asp57His
(OR 1.944) and Arg84Gly (OR 1.458), are associated with increased susceptibility
to infection while, Asp57Asn (OR 0) and Phe60Tyr (OR 0.453) are linked with
increased resistance to MAP infection in cattle.
Interferons: Interferons are inducible cytokines of multigene family.
Interferon-γ (IFN-γ) plays a crucial role in the innate host response
to intracellular bacteria, including mycobacteria (Huang
et al., 1993: Shtrichman and Samuel, 2001;
Mackintosh et al., 2011; Deb
and Goswami, 2011). Release of IFN-γ (protective Th1 response) after
the initial MAP entry into the host is considered as key factor in the control
of infection and manifestation of the disease (Coussens
et al., 2002; Coussens, 2004; Arsenault
et al., 2012; Dobson et al., 2013).
MAP infection is influenced by Interferon- γ gene (Pinedo
et al., 2009a). Increased gamma interferon (IFN-γ) expression
locally at the site of infection are reported in sub-clinical stage (Sweeney
et al., 1998) and higher IFN-γ production in culture supernatants
after stimulation of Peripheral Blood Mononuclear Cells (PBMC) with MAP antigens
(Stabel, 2000). With the shifting of MAP-infected animals
towards the clinical state, there is decrease in the production of local and
peripheral IFN-γ (Stabel, 2000, Sweeney
et al., 1998). Exogenous IFN-γ stimulates monocyte for destroying
the intracellular pathogen (Zhao et al., 1997).
A similar upregulation of IFN-γ production during the contained stage
of the tuberculosis has also been reported (Dlugovitzky
et al., 1997; Orme, 1993). Growth inhibition
of Mycobacterium tuberculosis and Mycobacterium bovis by macrophages
is observed due to addition of recombinant human IFN-γ to monocyte cell
cultures (Dlugovitzky et al., 1997; Orme,
1993). Conversely, infection of IFN-γ knockout mice with a sub-lethal
dose of Mycobacterium bovis or Mycobacterium tuberculosis resulted
in increased mortality and high bacteria counts from the organs viz., spleen,
liver and lung of recovered mice (Dalton et al.,
1993; Cooper et al., 1993).
Maintaining of mycobacteriosis within persistently infected macrophage and
activating newly required macrophages at sites of MAP infection require locally
high concentration of IFN-γ. High IFNγ responses are protective and
can play stimulatory effect on B lymphocyte and antibody production (Abbas
et al., 1996); sheep with pathological lesions and multibacillary
condition in intestine have been found to be IFN-γ negative (Perez
et al., 1999); also clinically infected cows had low IFNγ concentrations
compared to sub-clinically infected cows (Stabel, 2000).
It has been reported that IFNγ results found to be higher in cattle with
clinical paratuberculosis than sub-clinical (Billman-Jacobe
et al., 1992). Sub-clinical phase of MAP infection is characterized
by increasing IFNγ response while clinical paratuberculosis is characterized
by high antibody titre in blood, low IFNγ response and high bacterial shedding
in feces (Sohal et al., 2008).
TOLL-LIKE RECEPTORS GENES
Toll- Like Receptors (TLR) are a family of trans membrane structures capable
of recognizing several class of pathogens and are responsible for co-ordination
with appropriate innate and adaptive immune responses (Wang
et al., 2002; Quesniaux et al., 2004;
Ruiz-Larranaga et al., 2011; Purdie
et al., 2011) TLR4 mediates cytokine production and stimulates host
defense and is implicated in the recognition of mycobacterial antigens (Quesniaux
et al., 2004; Yadav and Schorey, 2006; Ferwerda
et al., 2007; Weiss et al., 2008;
Byun et al., 2012). Importance of TLRs in mycobacterial
recognition has been reviewed by Jo et al. (2007).
TLRs signaling occurs through MyD88 protein (Common adaptor protein) and studies
using MyD88-deficient mice revealed that TLRs are vital for launch of innate
response as mice were highly sensitive to infection with M. tuberculosis,
but MyD88 deficiency allowed emergence of adaptive responses (Ryffel
et al., 2006). Examination of TLR 1, 2 and 4 genes for the evidence
of polymorphism in test and control groups of three Slovakian cattle herds were
observed for all 3 genes, showing association with increased incidence of infection
in one case (TLR1) of polymorphism (Mucha et al.,
2009). Pinedo et al. (2009b). But there
is no association of TLR4 with infection (White et al.,
The TLR2-1903 T/C and some other TLR2 SNPs were significantly associated with
resistance to MAP and could be useful in marker-assisted breeding strategies
for the control of Johnes disease (Koets et al.,
2010). Additionally, the functional studies reported that genetic polymorphisms
in bovine TLR2 which result in higher macrophage activity may continue to enhance
T cell activation and a lower susceptibility to paratuberculosis. Another study
showed that chicken resistance to enteric bacteria like Salmonella infection
is coupled to TLR4. The magnitude of the TLR4 impact in the differential resistance
or susceptibility of chicken lines C and W1 is comparable thereto determined
with NRAMP1. Chickens carrying a minimum of one W1 (resistant) allele at NRAMP1
and TLR4 showed the best degree of resistance to infection (93% of the offspring
survived infection) compared to chickens bearing C alleles at NRAMP1 and TLR4
(58% survived the initial Ist week of infection). In this study, the odds ratio
for survival till day 7 is 0.62. In conjunction with NRAMP1, TLR4 explains 35
percent of the phenotypic variance and suggests that extra enteric bacteria
(Salmonella) resistance genes involved in innate or acquired immunity have yet
to be known within the chicken. A genome scan per-formed on the same backcross
panel verified the numerous linkage of these 2 loci with resistance to enteric
bacteria (Salmonella) infection within chickens confirming the approach of comparative
genomics to identify host resistance genes. The importance of TLR4 within the
host response of birds to infection with serovar Typhimurium must be additionally
explored; but the role of TLRs in the control of innate and adaptive immunity
makes them good targets for genetic intervention (Leveque
et al., 2003).
The SLC11A1 (Solute Carrier Family 11 member 1) gene (coding for Natural Resistance-Associated
Macrophage protein 1, NRAMP1) is the Bcg gene consists of 15 exons spanning
11.5 kb and encoding a 90-100 kDa membrane-bound protein containing 12 hydrophobic
transmembrane domains. It is associated with natural resistance against intracellular
bacteria viz., Mycobacterium spp., Salmonella spp. and protozoan
viz., Leishmania spp., playing an important role in innate defense mechanism,
preventing the bacterial growth in macrophages during the initial phase of infection
(Paixao et al., 2007). Profound differences
specifically due to susceptibility to SLC11A1 alleles was examined recently
in mouse as is the case with other pathogens (Roupie et
al., 2008; Korou et al., 2010). SLC11A1
functions being the part of the innate defense mechanism help in blocking of
bacterial replication during the early stages of infection but the associations
between SLC11A1 gene and MHC region was not reported in ovine JD (Reddacliff
et al., 2005).
Relationship between Polymorphisms in SLC11A1 has been linked to several autoimmune
diseases apart from mycobacterial infections. It has associated with leprosy
(Abel et al., 1998), tuberculosis (Bellamy
et al., 1998), rheumatoid arthritis (Ates
et al., 2009), visceral leishmaniasis (Mohamed
et al., 2003), multiple sclerosis (Kotze et
al., 2001), type 1 diabetes mellitus (Paccagnini
et al., 2009) and Inflammatory Bowel Disease (IBD) (Hofmeister
et al.,1997; Sechi et al., 2006;
Kotlowski et al., 2008; Gazouli
et al., 2008). Though SLC11A1 contains a number of single nucleotide
polymorphisms (SNPs) viz. SLC11A1 1730G>A (rs17235409; D543N) and SLC11A1
469+14G>C (rs3731865; INT4G>C), most of these disease associations have
been with a promoter dinucleotide microsatellite (GTn) that is known to affect
SLC11A1 expression levels (Searle and Blackwell, 1999).
SLC11A1 is a biologically plausible candidate risk gene for the handling and
elimination of intracellular pathogens due to its association with mycobacterial
diseases. Various studies counsel defects in genes concerned in microorganism
detection, handling and elimination are central to CD pathogenesis. Moreover
the assertion, albeit controversial that MAP is an initial trigger for CD provides
a further explanation to analyze SLC11A1 as a candidate risk gene for IBD. As
a result, this study had two aims. The first aim was to attempt the first of
the association of SLC11A1 1730G>A and SLC11A1 469+14G>C with IBD. The
second aim was to use previously collected MAP IS900 data (Bentley
et al., 2008) to test for association of SLC11A1 genotypes with occurrence
of MAP DNA in peripheral blood. Genotyping for SLC11A1 1730A>G and 469+14G>C
was done in 1468 (94.7%) and 1432 (92.4%) of study participants, correspondingly.
No deviations from HWE were found in cases or controls for either SNP (p>0.05).
Minor allele frequency (MAF) percentage of SLC11A1 1730G>A and SLC11A1 469+14G>C
was 2 and 30%, respectively. SLC11A1 SNP is not associated with overall CD,
UC or IBD susceptibility. Similarly, the minor allele and genotype frequencies
of SLC11A1 1730G>A and 469+14G>C is not associated with age at time of
onset of disease, behaviour of disease, its location, or any requirement of
surgical intervention. A significantly higher frequency of the SLC11A1 1730A
allele was seen in IBD patients who did not require immune-modulator therapy,
compared to those who did require this treatment approach (PIBD = 0.002, OR:
0.29, 95% CI: 0.13-0.66, PCD = 0.03, OR: 0.38, 95% CI: 0.15-0.95, PUC = 0.01,
OR: 0.75, 95% CI: 0.71-0.79). There was no significant association of SLC11A1
1730G>A with MAP status, whereas the SLC11A1 469+14C allele was associated
with increased incidence of MAP DNA in peripheral blood (p = 0.02, OR: 1.56,
95% CI: 1.06-2.23) (Stewart et al., 2010).
IL-10 is a cytokine that primarily acts as a negative feedback mechanism for
T lymphocytes and is as an essential immune-regulator in bacterial infection.
From the perspective of MAP infection, IL-10 prevents excessive Th1 and CD8+T
lymphocyte responses that may lead to immunopathology associated with infection
(Subharat et al., 2012; Coussens
et al., 2012). The cytokine also prevents overproduction of interleukins
4, 5 and 13. The IL-10 receptor alpha (IL-10Rα) gene encodes a ligand-binding
subunit of the IL-10R and therefore is a determinant of IL-10 responsiveness.
Interleukin-10 receptor alpha (IL10Rα) was considered as a candidate gene
for susceptibility of bovines to MAP infection, along with other Interleukin-10
(IL-10), based on associations of IL-10 promoter polymorphisms with inflammatory
bowel disease in humans (Verschoor et al., 2010a).
A total of six anonymous SNPs were identified in IL10Rα coding regions
and one of these was found to have a significant association with MAP infection
after correction for multiple testing (synonymous SNPs are alternative nucleotide
triplets that result in the coding of the same amino acid; they produce no change
in amino acid sequence of the protein and so are not functionally relevant).
The significant SNP was in high linkage disequilibrium with 3 other SNPs, meaning
the specific alleles of these 4 SNPs are inherited together as a group in most
cases and inheritance at 1 SNP provides the same information as any other.
IL-10R polymorphisms have been associated with bovine MAP infection status
(Verschoor et al., 2010a). Verchoor had conducted
a candidate gene-based study of MAP susceptibility sourcing Holstein cattle
from six commercial farms in Ontario with a history of high MAP prevalence.
The infection status was determined by ELISA, with 204 MAP positive and 242
healthy negative cattle included in the study. SNP discovery was performed for
IL-10 and its receptor subunits (IL-10Rα and IL-10Rβ), transforming
growth factor beta (TGFβ1) and its two receptors (TGFBR1 and 2) and SLC11A1.
SNP genotyping revealed tightly linked groups within the two sets of IL-10R
related SNP. Further haplotype analysis was carried out on IL-10R related SNP
only. Although a number of SNP were revealed for each gene only four tightly
linked SNP related to IL-10R (984G>A, 1098C>T, 1269T>C and 1302A>G)
showed statistically significant association with MAP infection, with a strong
additive and dominance relationship at the GCTA allele. Cattle with these polymorphisms
had a higher probability of MAP infection. None of the SNP from the other genes
tested demonstrated an association with MAP susceptibility in this study. Although
previous studies have correlated the action of IL-10 to the pathways of other
susceptibility related candidate genes (such as SLA11IA), this is the first
evidence of a susceptibility correlation with the IL-10 gene itself (Verschoor
et al., 2010a).
Intracellular pathogen resistance 1 (Ipr1) gene of murine model and human ortholog,
SP110 nuclear body protein has been reported to play an important role for inducing
innate immunity against Mycobacterium tuberculosis infection (Pan
et al., 2005; Liang et al., 2011;
Lei et al., 2012). Ruiz-Larranaga
et al. (2010) reported that SNP of SP110 gene are associated with
MAP infection in Holstein-Friesian cattle.
PEPTIDOGLYCAN RECOGNITION PROTEIN 1
Peptidoglycan recognition protein (PGRP) are a member of the mammalian innate
immune modules, consist of four molecules A, B, C and D with ligand binding
clefts situated at A-B and C-D contacts. PGRP binds to lipopolysaccharide (LPS),
peptidoglycan (PGN) and lipoteichoic acid (LTA) at their C-D contacts whereas
A-B contacts having binding site of fatty acids including mycolic acid of Mycobacterium
tuberculosis (Sharma et al., 2013). Holsteins
in South western and Eastern Ontario breeds were subjected for analysis for
the presence of any association between peptidoglycan recognition protein (PGRP)
and occurrence of MAP infection and it was observed that SNP c.480G>A of
PGRP are significantly associated with the occurrence of MAP (Pant
et al., 2011).
ANKRA2 AND CD180 GENES
Casas et al. (2011) also reported that SNP
in the ANKRA2 and CD180 genes were significantly associated with the presence
or absence of MAP in Brahman x Angus cattle.
WHOLE GENOME ASSOCIATION STUDIES
Whole Genome Association Studies (WGAS) take a global approach to comprehensively survey the genome of the species of interest for genetic markers associated with a disease or, infection phenotype. Results from WGAS provide information that can be used directly in predicting infection susceptibility genetics as well as providing the preliminary information on which positional candidate gene studies can be based (identification of narrow genomic location in which a gene responsible for susceptibility to infection resides). In Whole genome association studies enables definitive identification of allelic variations between and within diseased individuals or animals, their siblings and other members of family or associated ones.
There are one genome wide linkage analysis and four WGAS for MAP infection or related phenotypes in cattle using commercial dairy herd of Holstein Friesian cattle. Linkage analysis examine the association of alternative alleles inherited from parents in a defined family structure (e.g., often paternal half sib families in cattle), whereas WGAS consider association of alternative alleles at a given genetic marker using animals sampled broadly from the population.
The first genome-wide analysis for MAP infection done in cattle (Gonda
et al., 2007) was a linkage analysis considering the contribution
of alternative sire alleles. This study used 3 of the largest half sib families
(a total of 1263 daughters) from a larger Holstein resource population composed
of 4586 cows sired by 12 different bulls. In this study one chromosomal region
on bovine chromosome 20 was found significant at a chromosome-wise p<0.05.
Loss of information in estimating allele frequencies from pooled samples along
with use resource population partly; sole analysis of paternal genetic contribution
(within-family linkage analysis) instead of combined effects of linkage and
linkage disequilibrium and sparse marker density have restricted this study.
In the WGAS report of first MAP infection (Settles et
al., 2009), cows from 3 herds, in New York, Pennsylvania and Vermont
and were used in a case-control design. Phenotypic assessment of infection was
based on culture of MAP from tissue or lymph nodes of the small intestine or
from feces obtained at necropsy. A total of 218 animals were used in the study;
90 animals were classified as tissue positive and 41 out of them were classified
as fecal positive. In this study 16 SNPs showed associations exceeding a nominal
p<5x10-5 for the various case definition, though given the proximity
of some of the significant SNPs this represents 11 unique loci. For 3 of these
11, the association was observed for 2 case definitions. Subsequent re-analysis
of the same data considering tolerance as the phenotype where tolerance was
considered as the degree (quantitative) or presence or, absence (case control
analysis) of fecal shedding among animals were found to be tissue positive (Zanella
et al., 2011). SNP association with the tolerance phenotype that
exceeded a nominal p<5x10-5 were observed for 4 genomic locations.
A subsequent reanalysis of the same date set suggests an approach for identifying
potential candidate genes using data generated from WGAS (Neibergs
et al., 2010). In this study, SNP proximity to known genes was evaluated,
now considering the relative significance of groups of genes that are part of
specific mechanistic pathways or cascades. The advantage of this approach is
the multiple genes with modest effects that are part of a common pathway may
be discernible as a more significant group, whereas individually their effects
might be considered of insufficient significance for further analysis.
A second WGAS for susceptibility to MAP infection used cows (n = 232) from
6 dairy herds in Ontario with a prior history of a high prevalence of infection
(Pant et al., 2010), cases and controls in this
study were defined as animals positive (n = 90) or, negative (n = 142) to an
ELISA for serum antibodies. SNP studies were examined in a 2-stage logistic
regression analysis that first considered the effects of the SNPs nominally
significant in the preliminary analysis in the context of a chromosome through
a principal components approach. A total of 22 SNPs were significantly associated
with infection status, representing 13 unique chromosomal region, after accounting
for SNPs in close proximity that likely account for the same locus.
A third WGAS of susceptibility of MAP infection used cows from 119 herds in
the province of Lodi, Italy. Matching case (ELISA positive, n = 483) and control
(ELISA negative, n = 483) animals were sampled from the same herd on the same
day (Minozzi et al., 2010). Whole genome genotype
data were used to account for animal relationship in a mixed-model analysis
of SNP associations. Ten SNPs were significantly (p<5x10-5) associated
with the infection status representing 5 or, 6 unique chromosomal regions. Six
of these 10 SNPs were subsequently evaluated on a second group of case and control
animals from the same population (n = 277) and 5 of the 6 were significant at
a nominal p<0.01.
A fourth WGAS of susceptibility to MAP infection used 2 resource populations
of approximately 5000 each, the first including daughters of 12 specific Holstein
sires sampled from 300 cooperating herds across the United States and the second
including all cows from 6 cooperating herds in Wisconsin (Kirkpatrick
et al., 2010). The study used a unique approach of a case-reference
rather than the typical case control design. Given the extensive availability
of 50K SNP genotype data from artificial insemination sires and the availability
of pedigree information on the sampled animals, allele frequencies for cases
(positive for either blood ELISA or, fecal culture) were compared with allele
frequencies for AI sires representative of the herd or, population in question.
Use of this approach enabled genotyping of maximum number of case samples (n
= 521). Data from the 2 resource population were analyzed both separately and
jointly. The latter using a logistic regression approach. Multiple SNP model
included seven SNPs in unique chromosomal locations significant at p<5x10-5.
The cross validation analysis indicated that the models developed were only
fair predictors (correct prediction of sample rank 73% of the time), with the
caveat that the alternative grouping of samples was cases (ELISA and/or fecal
positive) versus reference (AI sires reflecting the general population). A comparison
of case and control (both ELISA and fecal negative) would likely yield an improved
CONCLUSIONS AND FUTURE PERSPECTIVES
The development of sub-clinical or clinical paratuberculosis or other chromic mycobacterial diseases is a result of a complex interaction between the host and pathogen. There are numerous host genes likely to be involved in the progression of disease caused by Mycobacterium avium subspecies paratuberculosis. Using the variety of study methods, substantial progress has already been made in advancing our understanding of genetic susceptibility or resistance to MAP infection. The identified molecular marker for resistance to Johnes disease will help in enhancing the overall herd resistance and immunity by encouraging the resistant animals for breeding (selective breeding for disease resistant traits). Similarly, genetic variations that contributes to host susceptibility to MAP infection is also very important both on reducing susceptibility to infection and for gaining a better understanding on the mechanisms of disease. Overall, the review may aid in designing the more efficacious, cost-effective and safer strategies for eradication of Johnes disease, especially in India, where there is rich diversity of genetic resources in terms of breeds and strain of domestic livestock in different agro-climatic zones. So, for the development of resistant breed of animals and control as well as elimination of paratuberculosis, much effort need to be implemented as there are likely to be many more novel genes to be identified. This review has more relevance in resource poor or resource-less developing and poor countries, where enough genetic variability exists in the animal population which may help to improve the productivity as well resistant against chronic and incurable infection like MAP and will be helpful in implementation of marker-assisted selective breeding programmes to control paratuberculosis. A delicate balance between breeding of domestic animals for production and for disease resistance to chronic infections like MAP may help to optimize productivity and reduce the levels MAP infection in domestic livestock as well as human population. If paratuberculosis control measures are not initiated, the endemicity of MAP and severity of disease will soon lead to shortage of food for burgeoning human population. Moreover, MAP infection is passes through generations via semen, milk and colostrum, will continue to increase the burden of disease in livestock population and non-activation during pasteurization will pose serious threat to human population of the country.
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