scholarly journals Tuberculosis Susceptibility and Vaccine Protection Are Independently Controlled by Host Genotype

mBio ◽  
2016 ◽  
Vol 7 (5) ◽  
Author(s):  
Clare M. Smith ◽  
Megan K. Proulx ◽  
Andrew J. Olive ◽  
Dominick Laddy ◽  
Bibhuti B. Mishra ◽  
...  
Keyword(s):  
Vaccine Efficacy ◽  
Inbred Mouse ◽  
Natural Populations ◽  
Model System ◽  
Mouse Strains ◽  
Host Genotype ◽  
Health Crisis ◽  
Host Genetics ◽  
Immunological Responses ◽  
Host Genetic

ABSTRACTThe outcome ofMycobacterium tuberculosisinfection and the immunological response to the bacillus Calmette-Guerin (BCG) vaccine are highly variable in humans. Deciphering the relative importance of host genetics, environment, and vaccine preparation for the efficacy of BCG has proven difficult in natural populations. We developed a model system that captures the breadth of immunological responses observed in outbred individual mice, which can be used to understand the contribution of host genetics to vaccine efficacy. This system employs a panel of highly diverse inbred mouse strains, consisting of the founders and recombinant progeny of the “Collaborative Cross” project. Unlike natural populations, the structure of this panel allows the serial evaluation of genetically identical individuals and the quantification of genotype-specific effects of interventions such as vaccination. When analyzed in the aggregate, our panel resembled natural populations in several important respects: the animals displayed a broad range of susceptibility toM. tuberculosis, differed in their immunological responses to infection, and were not durably protected by BCG vaccination. However, when analyzed at the genotype level, we found that these phenotypic differences were heritable.M. tuberculosissusceptibility varied between lines, from extreme sensitivity to progressiveM. tuberculosisclearance. Similarly, only a minority of the genotypes was protected by vaccination. The efficacy of BCG was genetically separable from susceptibility toM. tuberculosis, and the lack of efficacy in the aggregate analysis was driven by nonresponsive lines that mounted a qualitatively distinct response to infection. These observations support an important role for host genetic diversity in determining BCG efficacy and provide a new resource to rationally develop more broadly efficacious vaccines.IMPORTANCETuberculosis (TB) remains an urgent global health crisis, and the efficacy of the currently used TB vaccine,M. bovisBCG, is highly variable. The design of more broadly efficacious vaccines depends on understanding the factors that limit the protection imparted by BCG. While these complex factors are difficult to disentangle in natural populations, we used a model population of mice to understand the role of host genetic composition in BCG efficacy. We found that the ability of BCG to protect mice with different genotypes was remarkably variable. The efficacy of BCG did not depend on the intrinsic susceptibility of the animal but, instead, correlated with qualitative differences in the immune responses to the pathogen. These studies suggest that host genetic polymorphism is a critical determinant of vaccine efficacy and provide a model system to develop interventions that will be useful in genetically diverse populations.

scholarly journals Tuberculosis susceptibility and vaccine protection are independently controlled by host genotype

2016 ◽  
Author(s):  
Clare M. Smith ◽  
Megan K. Proulx ◽  
Andrew J. Olive ◽  
Dominick Laddy ◽  
Bibhuti B. Mishra ◽  
...  
Keyword(s):  
Vaccine Efficacy ◽  
Inbred Mouse ◽  
Natural Populations ◽  
Immunological Response ◽  
Model System ◽  
Mouse Strains ◽  
Host Genotype ◽  
Health Crisis ◽  
Host Genetics ◽  
Host Genetic

AbstractThe outcome ofMycobacterium tuberculosis(Mtb) infection and the immunological response to the Bacille Calmette Guerin (BCG) vaccine are highly variable in humans. Deciphering the relative importance of host genetics, environment, and vaccine preparation on BCG efficacy has proven difficult in natural populations. We developed a model system that captures the breadth of immunological responses observed in outbred individuals, which can be used to understand the contribution of host genetics to vaccine efficacy. This system employs a panel of highly-diverse inbred mouse strains, consisting of the founders and recombinant progeny of the “Collaborative Cross”. Unlike natural populations, the structure of this panel allows the serial evaluation of genetically-identical individuals and quantification of genotype-specific effects of interventions such as vaccination. When analyzed in the aggregate, our panel resembled natural populations in several important respects; the animals displayed a broad range of Mtb susceptibility, varied in their immunological response to infection, and were not durably protected by BCG vaccination. However, when analyzed at the genotype level, we found that these phenotypic differences were heritable. Mtb susceptibility varied between lines, from extreme sensitivity to progressive Mtb clearance. Similarly, only a minority of the genotypes was protected by vaccination. BCG efficacy was genetically separable from susceptibility, and the lack of efficacy in the aggregate analysis was driven by nonresponsive lines that mounted a qualitatively distinct response to infection. These observations support an important role for host genetic diversity in determining BCG efficacy, and provide a new resource to rationally develop more broadly efficacious vaccines.Importance:Tuberculosis (TB) remains an urgent global health crisis, and the efficacy of the currently used TB vaccine,M. bovisBCG, is highly variable. The design of more broadly-efficacious vaccines depends on understanding the factors that limit the protection imparted by BCG. While these complex factors are difficult to disentangle in natural populations, we used a model population of mice to understand the role of host genetic composition to BCG efficacy. We found that the ability of BCG to protect an individual genotype was remarkably variable. BCG efficacy did not depend on the intrinsic susceptibility of the animal, but instead correlated with qualitative differences in the immune response to the pathogen. These studies suggest that host genetic polymorphism is a critical determinant of vaccine efficacy and provides a model system to develop interventions that will be useful in genetically diverse populations.

scholarly journals H5N1 Influenza Virus Pathogenesis in Genetically Diverse Mice Is Mediated at the Level of Viral Load

mBio ◽  
2011 ◽  
Vol 2 (5) ◽  
Author(s):  
Adrianus C. M. Boon ◽  
David Finkelstein ◽  
Ming Zheng ◽  
Guochun Liao ◽  
John Allard ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Viral Load ◽  
H5n1 Virus ◽  
Inbred Mouse ◽  
Severe Disease ◽  
Mouse Strains ◽  
H5n1 Influenza Virus ◽  
Resistant Mouse ◽  
H5n1 Influenza ◽  
Host Genetic

ABSTRACTThe genotype of the host is one of several factors involved in the pathogenesis of an infectious disease and may be a key parameter in the epidemiology of highly pathogenic H5N1 influenza virus infection in humans. Gene polymorphisms may affect the viral replication rate or alter the host’s immune response to the virus. In humans, it is unclear which aspect dictates the severity of H5N1 virus disease. To identify the mechanism underlying differential responses to H5N1 virus infection in a genetically diverse population, we assessed the host responses and lung viral loads in 21 inbred mouse strains upon intranasal inoculation with A/Hong Kong/213/03 (H5N1). Resistant mouse strains survived large inocula while susceptible strains succumbed to infection with 1,000- to 10,000-fold-lower doses. Quantitative analysis of the viral load after inoculation with an intermediate dose found significant associations with lethality as early as 2 days postinoculation, earlier than any other disease indicator. The increased viral titers in the highly susceptible strains mediated a hyperinflamed environment, indicated by the distinct expression profiles and increased production of inflammatory mediators on day 3. Supporting the hypothesis that viral load rather than an inappropriate response to the virus was the key severity-determining factor, we performed quantitative real-time PCR measuring the cytokine/viral RNA ratio. No significant differences between susceptible and resistant mouse strains were detected, confirming that it is the host genetic component controlling viral load, and therefore replication dynamics, that is primarily responsible for a host’s susceptibility to a given H5N1 virus.IMPORTANCEHighly pathogenic H5N1 influenza virus has circulated in Southeast Asia since 2003 but has been confirmed in relatively few individuals. It has been postulated that host genetic polymorphisms increase the susceptibility to infection and severe disease. The mechanisms and host proteins affected during severe disease are unknown. Inbred mouse strains vary considerably in their ability to resist H5N1 virus and were used to identify the primary mechanism determining disease severity. After inoculation with H5N1, resistant mouse strains had reduced amounts of virus in their lungs, which subsequently resulted in lower production of proinflammatory mediators and less pathology. We therefore conclude that the host genetic component controlling disease severity is primarily influencing viral replication. This is an important concept, as it emphasizes the need to limit virus replication through antiviral therapies and it shows that the hyperinflammatory environment is simply a reflection of more viral genetic material inducing a response.

scholarly journals Dominant Effect Of Host Genetics On Skin Microbiota Composition In Homeostasis And Wound Healing

2021 ◽  
Author(s):  
Jack Galbraith ◽  
Julien Legrand ◽  
Nicholas Muller ◽  
Betoul Baz ◽  
Katie Togher ◽  
...  
Keyword(s):  
Wound Healing ◽  
Chronic Wounds ◽  
Statistical Significance ◽  
Inbred Mouse ◽  
Principal Component ◽  
Mouse Strains ◽  
Microbiota Composition ◽  
Skin Microbiota ◽  
Host Genetics ◽  
Mouse Genotype

Animal microbiota are shaped and maintained not only through microbiota-environmental interactions but also through host-microbiota interactions. The effects of the microbiota on the host has been the source of intense research in recent years, indicating a role for resident microbes in a range of conditions from obesity and mood disorders to atopic dermatitis and chronic wounds. Yet the ability of hosts to determine their microbiota composition is less well studied. In this study, we investigated the role host genetics plays in determining skin microbiota. We used 30 different mouse strains from the advanced recombinant inbred mouse panel, the Collaborative Cross, with PERMANOVA, GWAS and PCA-based GWAS analyses to demonstrate that murine skin microbiota composition is strongly dependent on murine strain. In particular, a quantitative trait locus on chromosome 4 associates both with Staphylococcus abundance and principal-component multi-trait analyses. Additionally, we used a full thickness excisional wound healing model to investigate the relative contributions from the skin microbiota and/or host genetics on wound healing speed. Wound associated changes in skin microbiota composition were observed and were in many instances host-specific. Despite reaching statistical significance, the wound-associated changes in skin microbiota accounted for only a small amount of the variance in wound healing speeds, with the majority attributable to mouse genotype (strain) and age. Host genetics has a significant impact on the skin microbiota composition during both homeostasis and wound healing. These findings have long reaching implications in our understanding of associations between microbiota dysbiosis and disease.

scholarly journals Genetic Factors in Animal Models of Intestinal Inflammation

1995 ◽  
Vol 9 (3) ◽  
pp. 147-152 ◽  
Author(s):  
R Balfour Sartor
Keyword(s):  
Genetic Susceptibility ◽  
Intestinal Inflammation ◽  
Dominant Role ◽  
Inbred Mouse ◽  
Bacterial Overgrowth ◽  
Human Leukocyte ◽  
Mouse Strains ◽  
Transgenic Rats ◽  
Immunological Mechanisms ◽  
Host Genetic

The critical importance of host genetic susceptibility in determining chronicity, aggressiveness and complications of intestinal inflammation is clearly demonstrated by studies of inbred rodents, transgenic rats and spontaneous mutants. Inbred Lewis rats challenged by purified bacterial cell wall polymers, indomethacin or small bowel bacterial overgrowth develop chronic granulomatous intestinal inflammation with fibrosis and extraintestinal manifestations, whereas Fischer (major histocompatibility complex identical to Lewis) and Buffalo rats identically stimulated demonstrate only self-limited enterocolitis with no chronic inflammation, fibrosis, granulomas or extraintestinal inflammation. Similar differential patterns of intestinal inflammation are apparent in inbred mouse strains challenged with trinitrobenzene-sulphonic acid,Citrobacter freundiior backcrossed with T cell receptor deficient (knockout) mice. The dominant role of genetic background in induction of intestinal inflammation is further documented by spontaneous colitis which develops in spontaneously mutant mice, cotton-top tamarins, human leukocyte antigen-B27/ β2 microglobulin transgenic rats and mice with targeted deletions of certain immunoregulatory cytokine and T lymphocyte genes. Identification of the immunological mechanisms of host genetic susceptibility and the genetic basis of spontaneous colitis should provide new insights into the pathogenesis of human inflammatory bowel disease.

A Mouse Model System for Genetic Analysis of Sociability: C57BL/6J Versus BALB/cJ Inbred Mouse Strains

2006 ◽  
Vol 59 (5) ◽  
pp. 415-423 ◽  
Author(s):  
Geena Mary V. Sankoorikal ◽  
Kristin A. Kaercher ◽  
Catherine J. Boon ◽  
Jin Kyoung Lee ◽  
Edward S. Brodkin
Keyword(s):  
Genetic Analysis ◽  
Mouse Model ◽  
Inbred Mouse ◽  
Model System ◽  
Mouse Strains ◽  
Inbred Mouse Strains ◽  
Mouse Model System

scholarly journals Inbred Strains Derived from Feral Mice Reveal New Pathogenic Mechanisms of Experimental Leishmaniasis Due to Leishmania major

2004 ◽  
Vol 72 (8) ◽  
pp. 4603-4611 ◽  
Author(s):  
Besma E. C. Babay ◽  
Hechmi Louzir ◽  
Chahnaz Kebaïer ◽  
Samir Boubaker ◽  
Koussay Dellagi ◽  
...  
Keyword(s):  
Leishmania Major ◽  
Inbred Mouse ◽  
Inbred Strains ◽  
Interleukin 4 ◽  
Mouse Strains ◽  
Suitable Model ◽  
Self Healing ◽  
Immunological Responses ◽  
Early Peak ◽  
Secondary Parasite

ABSTRACT Two inbred mouse strains, derived from feral founders, are susceptible to experimental leishmaniasis due to Leishmania major and support a disease of a severity intermediate between those observed in strains C57BL/6 and BALB/c. Mice of the MAI strain develop a severe, nonhealing, but nonfatal disease with no resistance to a secondary parasite challenge. The immunological responses showed a TH2 dominance characterized by an early peak of interleukin-4 (IL-4) and IL-13. However, neutralization of IL-4, which leads to a resistance phenotype in BALB/c mice, has no effect on disease progression in MAI mice. Mice of strain PWK develop a protracted but self-healing disease, characterized by a mixed TH1-plus-TH2 pattern of immune responses in which IL-10 plays an aggravating role, and acquire resistance to a secondary challenge. These features are close to those observed in human cutaneous leishmaniasis due to L. major and make PWK mice a suitable model for the human disease.

scholarly journals Prevalence ofToxoplasma gondiiin localized populations ofApodemus sylvaticusis linked to population genotype not to population location

Parasitology ◽  
2014 ◽  
Vol 142 (5) ◽  
pp. 680-690 ◽  
Author(s):  
J. BAJNOK ◽  
K. BOYCE ◽  
M. T. ROGAN ◽  
P. S. CRAIG ◽  
Z. R. LUN ◽  
...  
Keyword(s):  
Natural Populations ◽  
Spatial Location ◽  
Parasite Infection ◽  
Family Influence ◽  
Host Genotype ◽  
Wood Mice ◽  
Specific Pcr ◽  
Significant Difference ◽  
Host Genetic ◽  
Globally Distributed

SUMMARYToxoplasma gondiiis a globally distributed parasite infecting humans and warm-blooded animals. Although many surveys have been conducted forT. gondiiinfection in mammals, little is known about the detailed distribution in localized natural populations. In this study, host genotype and spatial location were investigated in relation toT. gondiiinfection. Wood mice (Apodemus sylvaticus) were collected from 4 sampling sites within a localized peri-aquatic woodland ecosystem. Mice were genotyped using standardA. sylvaticusmicrosatellite markers andT. gondiiwas detected using 4 specific PCR-based markers: SAG1, SAG2, SAG3 and GRA6 directly from infected tissue. Of 126 wood mice collected, 44 samples were positive giving an infection rate of 34·92% (95% CI: 27·14–43·59%). Juvenile, young adults and adults were infected at a similar prevalence, respectively, 7/17 (41·18%), 27/65 (41·54%) and 10/44 (22·72%) with no significant age-prevalence effect (P = 0·23). Results of genetic analysis of the mice showed that the collection consists of 4 genetically distinct populations. There was a significant difference inT. gondiiprevalence in the different genotypically derived mouse populations (P = 0·035) but not between geographically defined populations (P = 0·29). These data point to either a host genetic/family influence on parasite infection or to parasite vertical transmission.

Host genetic influences on the anthelmintic efficacy of papaya-derived cysteine proteinases in mice

Parasitology ◽  
2015 ◽  
Vol 142 (7) ◽  
pp. 989-998 ◽  
Author(s):  
WENCESLAUS LUOGA ◽  
FADLUL MANSUR ◽  
GILLIAN STEPEK ◽  
ANN LOWE ◽  
IAN R. DUCE ◽  
...  
Keyword(s):  
Standard Dose ◽  
Inbred Mouse ◽  
Mouse Strains ◽  
Intestinal Nematode ◽  
Anthelmintic Efficacy ◽  
Cimetidine Treatment ◽  
Heligmosomoides Bakeri ◽  
Host Genetic ◽  
Papaya Latex ◽  
Responder Mouse

SUMMARYEight strains of mice, of contrasting genotypes, infected with Heligmosomoides bakeri were studied to determine whether the anthelmintic efficacy of papaya latex varied between inbred mouse strains and therefore whether there is an underlying genetic influence on the effectiveness of removing the intestinal nematode. Infected mice were treated with 330 nmol of crude papaya latex or with 240 nmol of papaya latex supernatant (PLS). Wide variation of response between different mouse strains was detected. Treatment was most effective in C3H (90·5–99·3% reduction in worm counts) and least effective in CD1 and BALB/c strains (36·0 and 40·5%, respectively). Cimetidine treatment did not improve anthelmintic efficacy of PLS in a poor drug responder mouse strain. Trypsin activity, pH and PLS activity did not differ significantly along the length of the gastro-intestinal (GI) tract between poor (BALB/c) and high (C3H) drug responder mouse strains. Our data indicate that there is a genetic component explaining between-mouse variation in the efficacy of a standard dose of PLS in removing worms, and therefore warrant some caution in developing this therapy for wider scale use in the livestock industry, and even in human medicine.

scholarly journals Serial infection of diverse host ( Mus ) genotypes rapidly impedes pathogen fitness and virulence

2015 ◽  
Vol 282 (1798) ◽  
pp. 20141568 ◽  
Author(s):  
Jason L. Kubinak ◽  
Douglas H. Cornwall ◽  
Kim J. Hasenkrug ◽  
Frederick R. Adler ◽  
Wayne K. Potts
Keyword(s):  
Genetic Variation ◽  
Inbred Mice ◽  
Inbred Mouse ◽  
Viral Fitness ◽  
Single Infection ◽  
Mouse Strains ◽  
Host Genotype ◽  
Potent Inhibition ◽  
Single Host ◽  
Pathogen Fitness

Reduced genetic variation among hosts may favour the emergence of virulent infectious diseases by enhancing pathogen replication and its associated virulence due to adaptation to a limited set of host genotypes. Here, we test this hypothesis using experimental evolution of a mouse-specific retroviral pathogen, Friend virus (FV) complex. We demonstrate rapid fitness (i.e. viral titre) and virulence increases when FV complex serially infects a series of inbred mice representing the same genotype, but not when infecting a diverse array of inbred mouse strains modelling the diversity in natural host populations. Additionally, a single infection of a different host genotype was sufficient to constrain the emergence of a high fitness/high virulence FV complex phenotype in these experiments. The potent inhibition of viral fitness and virulence was associated with an observed loss of the defective retroviral genome (spleen focus-forming virus), whose presence exacerbates infection and drives disease in susceptible mice. Results from our experiments provide an important first step in understanding how genetic variation among vertebrate hosts influences pathogen evolution and suggests that serial exposure to different genotypes within a single host species may act as a constraint on pathogen adaptation that prohibits the emergence of more virulent infections. From a practical perspective, these results have implications for low-diversity host populations such as endangered species and domestic animals.

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