Genetic Factors in Animal Models of Intestinal Inflammation

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.

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

mBio ◽

10.1128/mbio.00171-11 ◽

2011 ◽

Vol 2 (5) ◽

Cited By ~ 41

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.

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Tuberculosis susceptibility and vaccine protection are independently controlled by host genotype

10.1101/064253 ◽

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.

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High monocyte to lymphocyte ratio is associated with impaired protection after subcutaneous administration of BCG in a mouse model of tuberculosis

F1000Research ◽

10.12688/f1000research.14239.2 ◽

2018 ◽

Vol 7 ◽

pp. 296

Author(s):

Andrea Zelmer ◽

Lisa Stockdale ◽

Satria A. Prabowo ◽

Felipe Cia ◽

Natasha Spink ◽

...

Keyword(s):

Mouse Model ◽

Tissue Distribution ◽

Inbred Mouse ◽

Subcutaneous Administration ◽

Mouse Strains ◽

Human Populations ◽

Early Assessment ◽

Vaccine Candidates ◽

Immunological Mechanisms ◽

Tissue Homogenates

Background:The only available tuberculosis (TB) vaccine, Bacillus Calmette-Guérin (BCG), has variable efficacy. New vaccines are therefore urgently needed. Why BCG fails is incompletely understood, and the tools used for early assessment of new vaccine candidates do not account for BCG variability. Taking correlates of risk of TB disease observed in human studies and back-translating them into mice to create models of BCG variability should allow novel vaccine candidates to be tested early in animal models that are more representative of the human populations most at risk. Furthermore, this could help to elucidate the immunological mechanisms leading to BCG failure. We have chosen the monocyte to lymphocyte (ML) ratio as a correlate of risk of TB disease and have back-translated this into a mouse model.Methods: Four commercially available, inbred mouse strains were chosen. We investigated their baseline ML ratio by flow cytometry; extent of BCG-mediated protection from Mycobacterium tuberculosisinfection by experimental challenge; vaccine-induced interferon gamma (IFNγ) response by ELISPOT assay; and tissue distribution of BCG by plating tissue homogenates.Results:The ML ratio varied significantly between A/J, DBA/2, C57Bl/6 and 129S2 mice. A/J mice showed the highest BCG-mediated protection and lowest ML ratio, while 129S2 mice showed the lowest protection and higher ML ratio. We also found that A/J mice had a lower antigen specific IFNγ response than 129S2 mice. BCG tissue distribution appeared higher in A/J mice, although this was not statistically significant.Conclusions:These results suggest that the ML ratio has an impact on BCG-mediated protection in mice, in alignment with observations from clinical studies. A/J and 129S2 mice may therefore be useful models of BCG vaccine variability for early TB vaccine testing. We speculate that failure of BCG to protect from TB disease is linked to poor tissue distribution in a ML high immune environment.

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

Parasitology ◽

10.1017/s003118201500013x ◽

2015 ◽

Vol 142 (7) ◽

pp. 989-998 ◽

Cited By ~ 1

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.

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High monocyte to lymphocyte ratio is associated with impaired protection after subcutaneous administration of BCG in a mouse model of tuberculosis

F1000Research ◽

10.12688/f1000research.14239.1 ◽

2018 ◽

Vol 7 ◽

pp. 296 ◽

Cited By ~ 1

Author(s):

Andrea Zelmer ◽

Lisa Stockdale ◽

Satria A. Prabowo ◽

Felipe Cia ◽

Natasha Spink ◽

...

Keyword(s):

Mouse Model ◽

Tissue Distribution ◽

Inbred Mouse ◽

Subcutaneous Administration ◽

Mouse Strains ◽

Human Populations ◽

Early Assessment ◽

Vaccine Candidates ◽

Immunological Mechanisms ◽

Tissue Homogenates

Background: The only available tuberculosis (TB) vaccine, Bacillus Calmette-Guérin (BCG), has variable efficacy. New vaccines are therefore urgently needed. Why BCG fails is incompletely understood, and the tools used for early assessment of new vaccine candidates do not account for BCG variability. Taking correlates of risk of TB disease observed in human studies and back-translating them into mice to create models of BCG variability should allow novel vaccine candidates to be tested early in animal models that are more representative of the human populations most at risk. Furthermore, this could help to elucidate the immunological mechanisms leading to BCG failure. We have chosen the monocyte to lymphocyte (ML) ratio as a correlate of risk of TB disease and have back-translated this into a mouse model. Methods: Four commercially available, inbred mouse strains were chosen. We investigated their baseline ML ratio by flow cytometry; extent of BCG-mediated protection from Mtb infection by experimental challenge; vaccine-induced interferon gamma (IFNγ) response by ELISPOT assay; and tissue distribution of BCG by plating tissue homogenates. Results: The ML ratio varied significantly between A/J, DBA/2, C57Bl/6 and 129S2 mice. A/J mice showed the highest BCG-mediated protection and lowest ML ratio, while 129S2 mice showed the lowest protection and higher ML ratio. We also found that A/J mice had a lower antigen specific IFNγ response than 129S2 mice. BCG tissue distribution appeared higher in A/J mice, although this was not statistically significant. Conclusions: These results suggest that the ML ratio has an impact on BCG-mediated protection in mice, in alignment with observations from clinical studies. A/J and 129S2 mice may therefore be useful models of BCG vaccine variability for early TB vaccine testing. We speculate that failure of BCG to protect from TB disease is linked to poor tissue distribution in a ML high immune environment.

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Genetic susceptibility to toxicologic lung responses among inbred mouse strains following exposure to carbon nanotubes and profiling of underlying gene networks

Toxicology and Applied Pharmacology ◽

10.1016/j.taap.2017.04.019 ◽

2017 ◽

Vol 327 ◽

pp. 59-70 ◽

Cited By ~ 2

Author(s):

Evan A. Frank ◽

Vinicius S. Carreira ◽

Kumar Shanmukhappa ◽

Mario Medvedovic ◽

Daniel R. Prows ◽

...

Keyword(s):

Carbon Nanotubes ◽

Genetic Susceptibility ◽

Gene Networks ◽

Inbred Mouse ◽

Mouse Strains ◽

Inbred Mouse Strains

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Tuberculosis Susceptibility and Vaccine Protection Are Independently Controlled by Host Genotype

mBio ◽

10.1128/mbio.01516-16 ◽

2016 ◽

Vol 7 (5) ◽

Cited By ~ 55

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.

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Host Genetic Variations and Sex Differences Potentiate Predisposition, Severity, and Outcomes of Group A Streptococcus-Mediated Necrotizing Soft Tissue Infections

Infection and Immunity ◽

10.1128/iai.01191-15 ◽

2015 ◽

Vol 84 (2) ◽

pp. 416-424 ◽

Cited By ~ 4

Author(s):

Karthickeyan Chella Krishnan ◽

Santhosh Mukundan ◽

Jeyashree Alagarsamy ◽

Donna Laturnus ◽

Malak Kotb

Keyword(s):

Sex Differences ◽

Soft Tissue ◽

Dominant Role ◽

Genetic Variations ◽

Mouse Strains ◽

Soft Tissue Infections ◽

Content Type ◽

Necrotizing Soft Tissue Infections ◽

Group A ◽

Host Genetic

Host genetic variations play an important role in several pathogenic diseases, and we previously provided strong evidence that these genetic variations contribute significantly to differences in susceptibility and clinical outcomes of invasive group AStreptococcus(GAS) patients, including sepsis and necrotizing soft tissue infections (NSTIs). The goal of the present study was to investigate how genetic variations and sex differences among four commonly used mouse strains contribute to variation in severity, manifestations, and outcomes of NSTIs. DBA/2J mice were more susceptible to NSTIs than C57BL/6J, BALB/c, and CD-1 mice, as exhibited by significantly greater bacteremia, excessive dissemination to the spleen, and significantly higher mortality. Differences in the sex of the mice also contributed to differences in disease severity and outcomes: DBA/2J female mice were relatively resistant compared to their male counterparts. However, DBA/2J mice exhibited minimal weight loss and developed smaller lesions than did the aforementioned strains. Moreover, at 48 h after infection, compared with C57BL/6J mice, DBA/2J mice had increased bacteremia, excessive dissemination to the spleen, and excessive concentrations of inflammatory cytokines and chemokines. These results indicate that variations in the host genetic context as well as sex play a dominant role in determining the severity of and susceptibility to GAS NSTIs.

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