Role Of Host Genetic Background Research Articles

HLA alleles associated with susceptibility and severity of the COVID-19 in Vietnamese

The diversity of clinical manifestations in COVID-19 has been observed not only among individuals but also among various populations in globally. HLA molecules play a central role in physiology, protective immunity, and deleterious, disease-related autoimmune reactivity or overreaction. This study exploited the association between HLA frequencies and SARS-CoV-2 susceptibility and disease severity among the Vietnamese cohort (159 patients and 52 controls). A significant difference in frequency of both HLA class I and II in mild, moderate, and severe/fatal COVID-19 patients and negative exposure individuals - the controls were observed. Regarding SARS-CoV-2 sensitivity, HLA-A*03:01, 30:01, HLA-DQA1*01:02, DRB1*15:01, and DRB5*02:02 presented higher frequency in the control group compared with infected patients but DRB1 09:01 frequency was higher in infected patients. Regarding COVID-19 severity, HLA‐F*01:01, 01:03 and DPA1*01:03 and 02:01, DPB1*04:01, DQA1*01:02, and DQB1*05:02 alleles were detected with higher frequency in severe patients but DOB*01:01, DRB1*05:01 and 09:01 had a significantly higher frequency in the mild group than remaining groups. Surprisingly, HLA-DQA1*01:02 and DRB1*09:01 alleles were identified with both inversely potential roles in protective function and severe risk. The obtained data herein will contribute to explore on the role of host genetic background in the pathology of COVID-19 disease.

Integrating single-cell RNA sequencing data to genome-wide association analysis data identifies significant cell types in influenza A virus infection and COVID-19.

With the global pandemic of COVID-19, the research on influenza virus has entered a new stage, but it is difficult to elucidate the pathogenesis of influenza disease. Genome-wide association studies (GWASs) have greatly shed light on the role of host genetic background in influenza pathogenesis and prognosis, whereas single-cell RNA sequencing (scRNA-seq) has enabled unprecedented resolution of cellular diversity and in vivo following influenza disease. Here, we performed a comprehensive analysis of influenza GWAS and scRNA-seq data to reveal cell types associated with influenza disease and provide clues to understanding pathogenesis. We downloaded two GWAS summary data, two scRNA-seq data on influenza disease. After defining cell types for each scRNA-seq data, we used RolyPoly and LDSC-cts to integrate GWAS and scRNA-seq. Furthermore, we analyzed scRNA-seq data from the peripheral blood mononuclear cells (PBMCs) of a healthy population to validate and compare our results. After processing the scRNA-seq data, we obtained approximately 70000 cells and identified up to 13 cell types. For the European population analysis, we determined an association between neutrophils and influenza disease. For the East Asian population analysis, we identified an association between monocytes and influenza disease. In addition, we also identified monocytes as a significantly related cell type in a dataset of healthy human PBMCs. In this comprehensive analysis, we identified neutrophils and monocytes as influenza disease-associated cell types. More attention and validation should be given in future studies.

Neonatal Multisystem Inflammatory Syndrome (MIS-N): The First Case Report in Thailand

Cases of multisystem inflammatory syndrome in children (MIS-C-like disease), have rarely been reported in neonates. A 33-week gestational age twin B female neonate presented with respiratory distress, tachycardia, and abdominal distention at 15 days of age. Echocardiogram found reduced left ventricular ejection fraction to 33%. Cardiac enzyme levels were all elevated: creatine kinase-MB 6.1 ng/mL (normal 0–4.5 ng/mL), troponin-T 170 ng/L (normal < 14 ng/L) and NT-proBNP > 35,000 pg/mL (normal 250.0 to 3987.0 pg/mL). Multiplex PCR of nasopharyngeal swab material was negative for respiratory pathogens. Serological tests revealed negative anti-spike SARS-CoV-2 IgM but positive anti-nucleocapsid SARS-CoV-2 IgG in both the mother and the patient. The mother provided a history of COVID-19 during pregnancy at 19 weeks gestation. The patient was diagnosed with neonatal multisystem inflammatory syndrome (MIS-N) and successfully treated with intravenous immunoglobulin (two doses of 1 gm/kg/dose) and methylprednisolone (2 mg/kg/day for 5 days then tapered off). She later developed coronary vessel (LMCA and RCA) dilation. The non-identical twin A did not develop MIS-N, suggesting a role of host genetic background. Newborn infants born to SARS-CoV-2-infected mothers at any time during pregnancy should be closely monitored for MIS-N. The optimal treatment approaches to this syndrome and the prognosis require further study.

Leveraging Single-Cell RNA-seq Data to Uncover the Association Between Cell Type and Chronic Liver Diseases.

BackgroundComponents of liver microenvironment is complex, which makes it difficult to clarify pathogenesis of chronic liver diseases (CLD). Genome-wide association studies (GWASs) have greatly revealed the role of host genetic background in CLD pathogenesis and prognosis, while single-cell RNA sequencing (scRNA-seq) enables interrogation of the cellular diversity and function of liver tissue at unprecedented resolution. Here, we made integrative analysis on the GWAS and scRNA-seq data of CLD to uncover CLD-related cell types and provide clues for understanding on the pathogenesis.MethodsWe downloaded three GWAS summary data and three scRNA-seq data on CLD. After defining the cell types for each scRNA-seq data, we used RolyPoly and LDSC-cts to integrate the GWAS and scRNA-seq. In addition, we analyzed one scRNA-seq data without association to CLD to validate the specificity of our findings.ResultsAfter processing the scRNA-seq data, we obtain about 19,002–32,200 cells and identified 10–17 cell types. For the HCC analysis, we identified the association between B cell and HCC in two datasets. RolyPoly also identified the association, when we integrated the two scRNA-seq datasets. In addition, we also identified natural killer (NK) cell as HCC-associated cell type in one dataset. In specificity analysis, we identified no significant cell type associated with HCC. As for the cirrhosis analysis, we obtained no significant related cell type.ConclusionIn this integrative analysis, we identified B cell and NK cell as HCC-related cell type. More attention and verification should be paid to them in future research.

Genetic variation in IL-10 influences the progression of hepatitis B infection

ObjectivesThe outcomes of hepatitis B virus (HBV) infection vary substantially among affected individuals, providing evidence of the role of host genetic background in the susceptibility to HBV persistence and the dynamics of liver injury progression to cirrhosis and hepatocellular carcinoma (HCC). MethodsSix single-nucleotide polymorphisms within the interleukin 10 gene (IL10) were genotyped by MALDI-TOF mass spectrometry in 857 patients with chronic HBV infection (CHB), 48 patients with resolved HBV infection, and 100 healthy volunteers. Associations of the selected polymorphisms with susceptibility to chronic HBV infection, liver injury progression, and outcomes were investigated. ResultsIL10 −819T (rs1800871), −592A (rs1800872), and +504T (rs3024490) alleles were associated with treatment-induced hepatitis B surface antigen (HBsAg) seroclearance. Additionally, IL10 ATAC haplotype increased the chance of HBsAg loss and was significantly more frequent in patients with less liver injury. Moreover rs1800871TT, rs1518110TT, rs1800872AA, and rs3024490TT genotypes were identified as predictors of a lower FIB-4 score (<0.5). ConclusionsThis study indicates that polymorphisms within the promoter region and intronic sequences of IL10 are associated with chronicity of hepatitis B and with HBV-induced liver damage.

Rearing background and exposure environment together explain higher survival of aquaculture fish during a bacterial outbreak

Abstract Parasitic diseases represent one of the greatest challenges for aquaculture worldwide and there is an increasing emphasis on ecological solutions to prevent infections. One proposed solution is enriched rearing, where traditional stimulus‐poor rearing tanks are equipped with different types of structures to increase habitat complexity. Such spatial enrichment is known to increase survival of fish during parasite epidemics, but the underlying mechanisms are still unclear. We studied whether enriched rearing affected infection of an important fish pathogen Flavobacterium columnare in young Atlantic salmon (Salmo salar) and sea‐migrating brown trout (Salmo trutta). First, we used natural bacterial exposures and multiple fish populations in a common garden experiment to address the role of host genetic background in effects of enriched rearing. Second, fish from standard and enriched rearing were experimentally exposed to controlled bacterial doses in standard and enriched environments in a full factorial design to explore the relative roles of rearing background and environment of exposure on survival of fish. Enriched rearing significantly increased survival of fish during the natural bacterial outbreak. This effect was also fairly consistent and observed in eight of the ten fish populations. In the controlled exposure, fish exposed in enriched environment had higher survival regardless of their rearing background, suggesting a stronger impact of the environment on the disease progression. Additionally, the survival in the enriched environment was the highest among the fish of enriched rearing background, supporting the idea of their higher resistance. Synthesis and applications. Our study suggests that the enhanced survival of fish in enriched rearing is a result of a combined effect of the environment and improved fish condition and, to a lesser degree, from host genetic background. This has important implications for when and how environmental enrichment should be applied. Overall, these results indicate that environmental enrichment has the potential to improve survival of fish during parasitic epidemics and thus reduce use of antibiotics in aquaculture.

Host genetic diversity influences the severity of Pseudomonas aeruginosa pneumonia in the Collaborative Cross mice.

BackgroundPseudomonas aeruginosa is one of the top three causes of opportunistic infections in humans. Patients with a compromised immune system, due to immunosuppressive therapies or underlying diseases such as cancer, AIDS or the hereditary disease cystic fibrosis, are at risk of developing P. aeruginosa infection. However, clinical evidence indicates extremely variable outcomes of P. aeruginosa infections in individuals at risk, suggesting that host multi-complex genetic traits may influence the severity of this opportunistic infection. Here, we have used an innovative experimental model to dissect whether host genetic background, such as those found in the outbred population, could influence the risk of morbidity and mortality to P. aeruginosa pneumonia.ResultsA highly genetically-diverse mouse resource population, Collaborative Cross (CC) mice, was infected with a clinical strain of P. aeruginosa and subsequently monitored for mortality, mean survival time, and morbidity, change in body weight for seven days post infection. Disease phenotypes ranged from complete resistance and recovery of body weight to lethal disease. Initial variables, including body weight, age and gender, have limited influence on P. aeruginosa outcome, emphasizing the role of host genetic background in defining the risk of morbidity and mortality. When broad-sense heritability of phenotypic traits was evaluated, it confirmed the influence of genetic profile rather than environmental factors among the CC lines during P. aeruginosa infection.ConclusionThis innovative model system can potentially reproduce the variables responses of disease severity observed in humans during P. aeruginosa pneumonia. Our results demonstrated that a widely-marked differential response to P. aeruginosa airway infection in term of morbidity and mortality, is mainly affected by host genetic factors, as multiple genetic loci or polymorphic variations.Electronic supplementary materialThe online version of this article (doi:10.1186/s12863-015-0260-6) contains supplementary material, which is available to authorized users.

Iron acts as a second signal during coinfection with M. tuberculosis and N. brasiliensis leading to exacerbated M. tuberculosis disease outcome (MPF1P.769)

Abstract Previously, our laboratory has demonstrated that N. brasiliensis (Nb), an intestinal helminth, is able to exacerbate Mtb burden in coinfected Balb/c mice through generation of alternatively activated macrophages (AAMs). To examine the role of host genetic background in infection we performed coinfection experiments in C57Bl/6 mice. In contrast to Balb/c, coinfected C57Bl/6 mice were able to control Mtb burden comparable to mice infected with Mtb alone, despite mounting a Th2 response. This led us to hypothesize that a factor in addition to the generation of AAMs was responsible for the increased Mtb burden seen in the coinfection model. Concurrent experiments designed to understand Mtb survival within in vitro derived AAMs showed that IL-4 and IL-13 treatment was insufficient to cause differences in Mtb growth, compared to untreated macrophages. However the addition of iron significantly increased Mtb growth in AAMs. Iron, besides being important for Mtb growth; is also present in the lungs following tissue damage caused by Nb larval migration. To determine the role of iron during Nb infection we evaluated the expression of iron responsive genes in the murine lungs at 3, 5, and 7 days post infection. Balb/c and C57Bl/6 mice exhibited distinct profiles in response to Nb infection consistent with iron recycling and iron sequestration, respectively. Future studies aim to further understand the role of iron as important cofactor in regulating bacterial burden during coinfection.

Experimental evolution of local parasite maladaptation

Sign and magnitude of local adaptation in host-parasite systems may vary with ecological, epidemiological or genetic parameters. To investigate the role of host genetic background, we established long-term experimental populations of different genotypes of the protozoan Paramecium caudatum, infected with the bacterial parasite Holospora undulata. We observed the evolution of an overall pattern of parasite local maladaptation for infectivity, indicating a general coevolutionary disadvantage of this parasite. Maladaptation extended to host populations with the same genetic background, similar to extending from the local to a higher regional level in natural populations. Patterns for virulence were qualitatively similar, but with less statistical support. A nonsignificant correlation with levels of (mal)adaptation for infectivity suggests independent evolution of these traits. Our results indicate similar (co)evolutionary trajectories in populations with different genetic backgrounds. Nonetheless, the correlated clines of genetic distance and parasite performance illustrate how genetic background can shape spatial gradients of local adaptation.

NK cell Activation during Acute Hepatitis C Virus Infection (45.18)

Abstract Genetic studies have implicated the inhibitory natural killer (NK) cell receptor KIR2DL3 and its human leukocyte antigen C group 1 (HLA-C1) ligand in resolution of hepatitis C virus (HCV) infection but a functional correlation was not established. To examine the role of NK cells during acute HCV, we have analyzed longitudinally the phenotype and function of NK cells from a cohort of patients following HCV exposure. Three groups with different infectious outcome were identified: spontaneous resolvers (SR), chronic evolution (C) and exposed un-infected (EU) (n=10 in each group). We have observed increased NK cell cytotoxicity (%CD107a+) in all groups suggesting NK cell activation following exposure but no correlation was established with infectious outcome. Nevertheless, we observed decreased expression of KIR2DL1, associated with highest NK cell inhibition, in SR. Furthermore, the highest IFN-γ production was observed in KIR2DL3+ NK cells, the least inhibited population, in all groups. Our results suggest that NK cell direct cytotoxicity might not be implicated in HCV clearance but that less NK cell inhibition is more frequent in SR patients. These results confirm the important role of host genetic background in NK cell function and provides the first demonstration of such a functional correlation in an in vivo infection setting. Research support: The Dana Foundation, CIHR, FRSQ, NCRTP-HepC

Bothrops jararaca venom (BjV) induces differential leukocyte accumulation in mice genetically selected for acute inflammatory reaction: The role of host genetic background on expression of adhesion molecules and release of endogenous mediators

The dynamics of the local inflammatory events induced by Bothrops jararaca venom (BjV) inoculation in footpad of mice genetically selected for maximal (AIRmax) and minimal (AIRmin) acute inflammatory reactivity (AIR) was investigated. The BjV injection induced a marked inflammatory cell infiltrate with predominance of neutrophils, with increased blood cell numbers before its accumulation, suggesting a stimulatory action of BjV on mechanisms of cell mobilization from bone marrow. The process of cell migration is regulated by different cell-adhesion molecules (CAM). Our results showed that neutrophil cells from both lines had the same pattern of response concerning CAMs expression, presenting the involvement of l-selectin, Mac-1 and PECAM-1 adhesion molecules in BjV-induced neutrophil accumulation. The effect of BjV on the release of pro-inflammatory cytokines and chemokines related with cellular migration was also studied and IL-1β, IL-6, TNF-α and MIP-2 levels could be detected after venom injection. The AIRmax mice were shown to be more responsive than AIRmin with respect to leukocyte influx, expression of MIP-2 and release of IL-1β and IL-6. These results demonstrate the importance of host genetic background in the local response and the involvement of alleles accumulated in AIRmax mice in the inflammatory events induced by BjV.

Trypanosoma cruzi: role of host genetic background in the differential tissue distribution of parasite clonal populations

Chagas' disease, caused by the protozoan parasite Trypanosoma cruzi, has quite a variable clinical presentation, ranging from asymptomatic to severe chronic cardiac and/or gastrointestinal disease. The reason for that is not completely understood, but both parasite and host genetic traits are certainly involved. Recently, we have demonstrated clinically and experimentally that the genetic variability of T. cruzi is one of the determinants of the pattern of tissue involvement in Chagas' disease. We then decided to turn our attention to the role of host genetic background. To study this, we compared the infection of four lineages of mice [three inbred (BALB/c, DBA-2, and c57Black/6) and one outbred (Swiss)] with two T. cruzi clonal populations, the Col1.7G2 clone and the JG monoclonal strain. The tissue distribution of T. cruzi strains was identical for BALB/c and DBA-2 mice, but very different in C57BL/6 (H-2 b) and outbred Swiss mice. This result clearly demonstrates the importance of host genetic aspects in the process. Since BALB/c and DBA-2 have the same H-2 haplotype (H-2 d) and C57BL/6 does not (H-2 b), it is possible that MHC variability may be involved in influencing the tissue distribution of involvement in experimental Chagas' disease of the mouse. Abbreviations: PCR, polymerase chain reaction; LSSP-PCR, low-stringency single specific primer PCR; kDNA, kinetoplast DNA; MHC, major histocompatibility complex; dNTP, 2 ′-deoxynucleotide 5 ′-triphosphate

Prevalence of CCR2-64I, SDF1-3'A and CCR5-Delta32 alleles in healthy Thais.

A genetic survey was performed of 200 healthy Thai blood donors for the frequency of three alleles that influence susceptibility to HIV infection and the rate of progression to HIV disease. The CCR5-Delta32 allele was not detected in this population. The CCR2-64I allele was detected at a frequency similar to that found in other Asian populations (15.7%). SDF1-3'A was detected at 33.2%, supporting a cline of increasing frequency of this allele from African and Caucasian to Asian (particularly Australasian) populations. These results have implications for the role of host genetic background in the biology and pathology of HIV in Thailand, and indicate that a systematic survey of non-Caucasian populations may reveal novel alleles important in HIV disease.

Association between HLA‐DQB1 alleles and risk for cervical cancer in African‐American women

Squamous-cell carcinoma of the cervix and its precursor lesions are associated with human papillomavirus (HPV) infection. Epidemiological studies indicate that HPV infection in itself is not sufficient for cervical-cancer induction, suggesting that other factors contribute to carcinogenesis. We have investigated the potential role of host genetic background as one such factor. We screened a series of squamous-cell carcinomas of the cervix for HLA-class-II DQB1* alleles by the polymerase chain reaction and site-specific oligonucleotide probe hybridization and for HPV type from African-American women using a local, ethnically matched control panel. Statistically significant associations for increase in relative risk for cervical cancer were seen for DQB1*0303 and DQB1*0604. DQB1*0201 and the heterozygote DQB1*0301/*0501 showed a decrease in relative risk for cervical cancer. HPV typing revealed no association between virus type and DQB1 alleles. Our results confirm other studies showing an increase in relative risk for cervical cancer associated with HLA-DQ3 alleles in Caucasians.