Host genetics and population structure effects on parasitic disease

Host genetic factors exert significant influences on differential susceptibility to many infectious diseases. In addition, population structure of both host and parasite may influence disease distribution patterns. In this study, we assess the effects of population structure on infectious disease in two populations in which host genetic factors influencing susceptibility to parasitic disease have been extensively studied. The first population is the Jirel population of eastern Nepal that has been the subject of research on the determinants of differential susceptibility to soil-transmitted helminth infections. The second group is a Brazilian population residing in an area endemic for Trypanosoma cruzi infection that has been assessed for genetic influences on differential disease progression in Chagas disease. For measures of Ascaris worm burden, within-population host genetic effects are generally more important than host population structure factors in determining patterns of infectious disease. No significant influences of population structure on measures associated with progression of cardiac disease in individuals who were seropositive for T. cruzi infection were found.     

Socio-Cultural Aspects of Chagas Disease: A Systematic Review of Qualitative Research

Background

Globally, more than 10 million people are infected with Trypanosoma cruzi, which causes about 20 000 annual deaths. Although Chagas disease is endemic to certain regions of Latin America, migratory flows have enabled its expansion into areas where it was previously unknown. Economic, social and cultural factors play a significant role in its presence and perpetuation. This systematic review aims to provide a comprehensive overview of qualitative research on Chagas disease, both in endemic and non-endemic countries.

Methodology/Principal Findings

Searches were carried out in ten databases, and the bibliographies of retrieved studies were examined. Data from thirty-three identified studies were extracted, and findings were analyzed and synthesized along key themes. Themes identified for endemic countries included: socio-structural determinants of Chagas disease; health practices; biomedical conceptions of Chagas disease; patient''s experience; and institutional strategies adopted. Concerning non-endemic countries, identified issues related to access to health services and health seeking.

Conclusions

The emergence and perpetuation of Chagas disease depends largely on socio-cultural aspects influencing health. As most interventions do not address the clinical, environmental, social and cultural aspects jointly, an explicitly multidimensional approach, incorporating the experiences of those affected is a potential tool for the development of long-term successful programs. Further research is needed to evaluate this approach.     

A Parent-of-Origin Effect Determines the Susceptibility of a Non-Informative F1 Population to Trypanosoma cruzi Infection In Vivo

The development of Chagas disease is determined by a complex interaction between the genetic traits of both the protozoan parasite, T. cruzi, and the infected host. This process is regulated by multiple genes that control different aspects of the host-parasite interaction. While determination of the relevant genes in humans is extremely difficult, it is feasible to use inbred mouse strains to determine the genes and loci responsible for host resistance to infection. In this study, we investigated the susceptibility of several inbred mouse strains to infection with the highly virulent Y strain of T. cruzi and found a considerable difference in susceptibility between A/J and C57BL/6 mice. We explored the differences between these two mouse strains and found that the A/J strain presented higher mortality, exacerbated and uncontrolled parasitemia and distinct histopathology in the target organs, which were associated with a higher parasite burden and more extensive tissue lesions. We then employed a genetic approach to assess the pattern of inheritance of the resistance phenotype in an F1 population and detected a strong parent-of-origin effect determining the susceptibility of the F1 male mice. This effect is unlikely to result from imprinted genes because the inheritance of this susceptibility was affected by the direction of the parental crossing. Collectively, our genetic approach of using the F1 population suggests that genes contained in the murine chromosome X contribute to the natural resistance against T. cruzi infection. Future linkage studies may reveal the locus and genes participating on the host resistance process reported herein.     

The evolutionary effect of endemic infectious disease: Continuous models for an invariant pathogen

Continuous deterministic models are used to investigate the relationship between the epidemiology of endemic infectious disease and the genetics of natural selection in the host population when a specific genetic locus controls susceptibility to disease under a variety of circumstances. One locus, two allele genes are considered in the contexts of haploid and diploid host populations while the agent of infection is assumed to be invariant. It is found that polymorphic equilibria exist and are stable for certain parameter combinations in each of the cases studied. The equilibrium levels of gene frequencies and disease prevalence depend on both genetic and epidemic factors.     

Genetic susceptibility to infection with human papillomavirus and development of cervical cancer in women in Brazil

Human papillomavirus (HPV) is considered to be a necessary but not sufficient cause for cervical cancer and, therefore, other factors contribute to the carcinogenic process. A hereditary component for this neoplasia has been reported and several studies indicate that genetic background of the host is important for cervical cancer susceptibility. Among genetic factors that could participate in the susceptibility to this tumor and disease outcome, polymorphic genes of the major histocompatibility complex (MHC), as well as a particular polymorphism in the p53 gene have been intensely investigated. From our analysis of 613 samples in Brazil, we found evidence to indicate that different polymorphic human leukocyte antigen (HLA) genes are involved in the clearance and maintenance of HPV infection. In addition, the homozygous codon 72 p53-Arg gene allele is associated with susceptibility to HPV-associated cervical carcinogenesis. However, supportive and opposing data have been reported in different populations. Therefore, international collaborative studies need to be conducted to define the consistency of the associations described.     

Genome-wide analysis of polymorphisms associated with cytokine responses in smallpox vaccine recipients

The role that genetics play in response to infection or disease is becoming increasingly clear as we learn more about immunogenetics and host-pathogen interactions. Here we report a genome-wide analysis of the effects of host genetic variation on cytokine responses to vaccinia virus stimulation in smallpox vaccine recipients. Our data show that vaccinia stimulation of immune individuals results in secretion of inflammatory and Th1 cytokines. We identified multiple SNPs significantly associated with variations in cytokine secretion. These SNPs are found in genes with known immune function, as well as in genes encoding for proteins involved in signal transduction, cytoskeleton, membrane channels and ion transport, as well as others with no previously identified connection to immune responses. The large number of significant SNP associations implies that cytokine secretion in response to vaccinia virus is a complex process controlled by multiple genes and gene families. Follow-up studies to replicate these findings and then pursue mechanistic studies will provide a greater understanding of how genetic variation influences vaccine responses.     

Host genetic factors in American cutaneous leishmaniasis: a critical appraisal of studies conducted in an endemic area of Brazil

American cutaneous leishmaniasis (ACL) is a vector-transmitted infectious disease with an estimated 1.5 million new cases per year. In Brazil, ACL represents a significant public health problem, with approximately 30,000 new reported cases annually, representing an incidence of 18.5 cases per 100,000 inhabitants. Corte de Pedra is in a region endemic for ACL in the state of Bahia (BA), northeastern Brazil, with 500-1,300 patients treated annually. Over the last decade, population and family-based candidate gene studies were conducted in Corte de Pedra, founded on previous knowledge from studies on mice and humans. Notwithstanding limitations related to sample size and power, these studies contribute important genetic biomarkers that identify novel pathways of disease pathogenesis and possible new therapeutic targets. The present paper is a narrative review about ACL immunogenetics in BA, highlighting in particular the interacting roles of the wound healing gene FLI1 with interleukin-6 and genes SMAD2 and SMAD3 of the transforming growth factor beta signalling pathway. This research highlights the need for well-powered genetic and functional studies on Leishmania braziliensis infection as essential to define and validate the role of host genes in determining resistance/susceptibility regarding this disease.     

Genetic factors in iodine deficiency disorders: a general review

This review presents a summary of what is known about genetic factors possibly involved in iodine deficiency disorders. After an overview on thyroid iodine metabolism and the role of environmental factors in endemic goitre, we analyse genetic studies on endemic goitre reported in the literature. We hypothesize that endemic goitre is a multifactorial disease in which the major factor would be of environmental nature (iodine deficiency) with a lesser role for genetic factors. Mutations, in a heterozygote state, of one of the genes involved in tiered hormonogenesis could lead to a less effective metabolic pathway in the iodine transport or hormonogenesis. We also briefly review various hereditary disorders which may be involved in endemic goitre. Then, we postulate that the presence of some genetic variants in the population or the heterozygote status of individuals for thyroid hereditary disorders may influence the degree of the thyroid enlargement and/or hypothyroidism.     

Severity of chronic Chagas disease is associated with cytokine/antioxidant imbalance in chronically infected individuals

Understanding the pathogenic mechanisms in chronic Chagas disease, a major cause of morbidity and mortality in Latin America, is essential for the design of rational therapeutic strategies. In this paper we show that the development of Chagas disease is a consequence of a long-term and complex relationship between parasite persistence and maladapted homeostatic mechanisms in the host which leads to pathologic changes. We performed a retrospective study on 50 patients with chronic Chagas disease and 50 healthy control individuals. The specific immune response was detected by ELISA and IHA tests using autochthonous antigens, inflammatory process with the cytokine tumour necrosis factor (TNF)-alpha and nitric oxide (NO), and antioxidant protection with glutathione peroxidase and superoxide dismutase (SOD) levels. We developed generalised linear modelling procedures to assess simultaneously which explanatory variables and/or their interactions better explained disease severity in patients. Our results show the existence of a strong relationship between anti-Trypanosoma cruzi levels and chronic Chagas disease (P<0.0001). Taken together, the statistical data indicate both cumulative and complementary effects, where the increase in TNF-alpha (P=0.004) and NO (P=0.005) levels correlated with a reduction in glutathione peroxidase (P=0.0001) and SOD (P=0.01) levels drives the disease pathology in chronically infected patients. Our findings may have important implications for understanding host susceptibility to develop severe chronic infectious disease. In addition we show putative targets for the design of new therapeutic strategies to prevent disease progression, considering both specific treatment against the aetiological agent and modulation of the different immunopathological reactions in chronically infected individuals with chronic Chagas disease.     

Genome-informed approach to identify genetic determinants of Flavobacterium psychrophilum phage susceptibility

The fish pathogen Flavobacterium psychrophilum infects farmed salmonids worldwide, and application of bacteriophages has been suggested for controlling disease outbreaks in aquaculture. Successful application of phages requires detailed knowledge about the variability in phage susceptibility of the host communities. In this study, we analysed the genetic diversity of F. psychrophilum hosts and phages from the Baltic Sea area to identify genetic determinants of phage-host interaction patterns. A host range analysis of 103 phages tested against 177 F. psychrophilum strains (18 231 phage–host interactions) identified nine phage clusters, infecting from 10% to 91% of the strain collection. The core genome-based comparison of 35 F. psychrophilum isolates revealed an extremely low overall genomic diversity (>99.5% similarity). However, a small subset of 16 ORFs, including genes involved in the type IX secretion system (T9SS), gliding motility and hypothetical cell-surface related proteins, exhibited a highly elevated genetic diversity. These specific genetic variations were linked to variability in phage infection patterns obtained from experimental studies, indicating that these genes are key determinants of phage susceptibility. These findings provide novel insights on the molecular mechanisms determining phage susceptibility in F. psychrophilum and emphasizes the importance of phages as drivers of core genomic diversity in this pathogen.     

Chemokines,inflammation and Trypanosoma cruzi infection

The inflammatory response that follows the infection with Trypanosoma cruzi is essential for host resistance to infection but is also responsible for the diverse pathology observed in Chagas disease. Here, we examine the stimuli and mechanisms underlying chemokine production following infection in vitro and in vivo, and the ability of chemokines to coordinate the influx of inflammatory and immune cells to the site of parasite infection, and to control T. cruzi growth.     

Genetic diversity in cytokines associated with immune variation and resistance to multiple pathogens in a natural rodent population

Pathogens are believed to drive genetic diversity at host loci involved in immunity to infectious disease. To date, studies exploring the genetic basis of pathogen resistance in the wild have focussed almost exclusively on genes of the Major Histocompatibility Complex (MHC); the role of genetic variation elsewhere in the genome as a basis for variation in pathogen resistance has rarely been explored in natural populations. Cytokines are signalling molecules with a role in many immunological and physiological processes. Here we use a natural population of field voles (Microtus agrestis) to examine how genetic diversity at a suite of cytokine and other immune loci impacts the immune response phenotype and resistance to several endemic pathogen species. By using linear models to first control for a range of non-genetic factors, we demonstrate strong effects of genetic variation at cytokine loci both on host immunological parameters and on resistance to multiple pathogens. These effects were primarily localized to three cytokine genes (Interleukin 1 beta (Il1b), Il2, and Il12b), rather than to other cytokines tested, or to membrane-bound, non-cytokine immune loci. The observed genetic effects were as great as for other intrinsic factors such as sex and body weight. Our results demonstrate that genetic diversity at cytokine loci is a novel and important source of individual variation in immune function and pathogen resistance in natural populations. The products of these loci are therefore likely to affect interactions between pathogens and help determine survival and reproductive success in natural populations. Our study also highlights the utility of wild rodents as a model of ecological immunology, to better understand the causes and consequences of variation in immune function in natural populations including humans.     

Molecular Neuro-Pathomechanism of Neurocysticercosis: How Host Genetic Factors Influence Disease Susceptibility

Neurocysticercosis (NCC) is one of the most neglected tropical diseases among widely endemic neurological diseases. It is caused by cysticerci of Taenia solium. The clinical symptom for the outcome of infection and progression of disease is pleomorphic and its neuro-pathomechanism is still illusive. Identification of host genetic factors and their association with disease susceptibility is one of the most important areas of research towards personalized medicine in the era of omics. Several genes and their allelic variations had been identified to be associated with various neurological disorders; however, the information for parasitic diseases affecting the central nervous system is very limited. Both Th1 and Th2 arms of the immune system are reported to be active at different stages of T. solium infection in the brain. Recently, several papers had been published, where the role of host genetic makeup with NCC had been explored. Increased frequency of HLA-A28, HLA-B63, HLA-B58, TLR 4 Asp299Gly, sICAM-1 gene K469E, GSTM1, and GSTT1 were found to be associated with increased risk of NCC occurrence, while HLA-DQW2 and HLA-A11 were shown to be providing protection from disease. In this review, we have summarized these findings and analyzed the influence of host genetic polymorphism on the susceptibility/resistance of host to NCC.     

A unifying theory for genetic epidemiological analysis of binary disease data

Background

Genetic selection for host resistance offers a desirable complement to chemical treatment to control infectious disease in livestock. Quantitative genetics disease data frequently originate from field studies and are often binary. However, current methods to analyse binary disease data fail to take infection dynamics into account. Moreover, genetic analyses tend to focus on host susceptibility, ignoring potential variation in infectiousness, i.e. the ability of a host to transmit the infection. This stands in contrast to epidemiological studies, which reveal that variation in infectiousness plays an important role in the progression and severity of epidemics. In this study, we aim at filling this gap by deriving an expression for the probability of becoming infected that incorporates infection dynamics and is an explicit function of both host susceptibility and infectiousness. We then validate this expression according to epidemiological theory and by simulating epidemiological scenarios, and explore implications of integrating this expression into genetic analyses.

Results

Our simulations show that the derived expression is valid for a range of stochastic genetic-epidemiological scenarios. In the particular case of variation in susceptibility only, the expression can be incorporated into conventional quantitative genetic analyses using a complementary log-log link function (rather than probit or logit). Similarly, if there is moderate variation in both susceptibility and infectiousness, it is possible to use a logarithmic link function, combined with an indirect genetic effects model. However, in the presence of highly infectious individuals, i.e. super-spreaders, the use of any model that is linear in susceptibility and infectiousness causes biased estimates. Thus, in order to identify super-spreaders, novel analytical methods using our derived expression are required.

Conclusions

We have derived a genetic-epidemiological function for quantitative genetic analyses of binary infectious disease data, which, unlike current approaches, takes infection dynamics into account and allows for variation in host susceptibility and infectiousness.