scholarly journals Variation in Host Resistance to Blastomyces dermatitidis: Potential Use of Genetic Reference Panels and Advances in Immunophenotyping of Diverse Mouse Strains

mBio ◽  
2022 ◽  
Author(s):  
Elaine M. Kohn ◽  
Cleison Taira ◽  
Hanah Dobson ◽  
Lucas Dos Santos Dias ◽  
Uju Okaa ◽  
...  
Keyword(s):  
Genetic Variation ◽  
Infectious Diseases ◽  
Fungal Infection ◽  
Host Resistance ◽  
Blastomyces Dermatitidis ◽  
Mouse Strains ◽  
Dimorphic Fungi ◽  
Host Genetic ◽  
Potential Use

Host genetic variation significantly impacts vulnerability to infectious diseases. While host variation in susceptibility to fungal infection with dimorphic fungi has long been recognized, genes that underpin this variation are poorly understood.

scholarly journals An assessment of opportunities to dissect host genetic variation in resistance to infectious diseases in livestock

animal ◽  
2009 ◽  
Vol 3 (3) ◽  
pp. 415-436 ◽  
Author(s):  
G. Davies ◽  
S. Genini ◽  
S.C. Bishop ◽  
E. Giuffra
Keyword(s):  
Genetic Variation ◽  
Infectious Diseases ◽  
Host Genetic

scholarly journals The genetic architecture of human infectious diseases and pathogen-induced cellular phenotypes

2020 ◽  
Author(s):  
Andrew T Hale ◽  
Dan Zhou ◽  
Rebecca L Sale ◽  
Lisa Bastarache ◽  
Liuyang Wang ◽  
...  
Keyword(s):  
Genetic Variation ◽  
Infectious Diseases ◽  
Molecular Mechanisms ◽  
Causal Effect ◽  
Association Studies ◽  
Rrna Gene ◽  
Pathogen Invasion ◽  
Gene Level ◽  
Host Genetic ◽  
Cellular Phenotypes

Infectious diseases (ID) represent a significant proportion of morbidity and mortality across the world. Host genetic variation is likely to contribute to ID risk and downstream clinical outcomes, but there is a need for a genetics-anchored framework to decipher molecular mechanisms of disease risk, infer causal effect on potential complications, and identify instruments for drug target discovery. Here we perform transcriptome-wide association studies (TWAS) of 35 clinical ID traits in a cohort of 23,294 individuals, identifying 70 gene-level associations with 26 ID traits. Replication in two large-scale biobanks provides additional support for the identified associations. A phenome-scale scan of the 70 gene-level associations across hematologic, respiratory, cardiovascular, and neurologic traits proposes a molecular basis for known complications of the ID traits. Using Mendelian Randomization, we then provide causal support for the effect of the ID traits on adverse outcomes. The rich resource of genetic information linked to serologic tests and pathogen cultures from bronchoalveolar lavage, sputum, sinus/nasopharyngeal, tracheal, and blood samples (up to 7,699 positive pathogen cultures across 92 unique genera) and a large catalog of genome-wide associations of microbiome variation generated from phylogenetic analysis of 16S rRNA gene sequences are developed here into a platform to interrogate the genetic basis of compartment-specific infection and colonization. To accelerate insights into cellular mechanisms, we develop a TWAS repository of gene-level associations in a broad collection of human tissues with 79 pathogen-exposure induced cellular phenotypes as a discovery and replication platform. Cellular phenotypes of infection by 8 pathogens included pathogen invasion, intercellular spread, cytokine production, and pyroptosis. These rich datasets will facilitate mechanistic insights into the role of host genetic variation on ID risk and pathophysiology, with important implications for our molecular understanding of potentially severe phenotypic outcomes.

scholarly journals Implications of Host Genetic Variation on the Risk and Prevalence of Infectious Diseases Transmitted Through the Environment

Genetics ◽  
2011 ◽  
Vol 188 (3) ◽  
pp. 683-693 ◽  
Author(s):  
Andrea B. Doeschl-Wilson ◽  
R. Davidson ◽  
J. Conington ◽  
T. Roughsedge ◽  
M. R. Hutchings ◽  
...  
Keyword(s):  
Genetic Variation ◽  
Infectious Diseases ◽  
Host Genetic

scholarly journals Temporal and Anatomical Host Resistance to Chronic Salmonella Infection Is Quantitatively Dictated by Nramp1 and Influenced by Host Genetic Background

PLoS ONE ◽  
2014 ◽  
Vol 9 (10) ◽  
pp. e111763 ◽  
Author(s):  
Wendy P. Loomis ◽  
Matthew L. Johnson ◽  
Alicia Brasfield ◽  
Marie-Pierre Blanc ◽  
Jaehun Yi ◽  
...  
Keyword(s):  
Host Resistance ◽  
Genetic Background ◽  
Salmonella Infection ◽  
Host Genetic

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.

Potential use of biomarkers for the clinical evaluation of sarcoidosis

2021 ◽  
pp. jim-2020-001659
Author(s):  
Amir Mousapasandi ◽  
Cristan Herbert ◽  
Paul Thomas
Keyword(s):  
Clinical Evaluation ◽  
Clinical Presentation ◽  
Current Knowledge ◽  
Epithelioid Cell ◽  
Pulmonary Sarcoidosis ◽  
Biological Molecules ◽  
Unknown Etiology ◽  
Chronic Antigenic Stimulation ◽  
Host Genetic ◽  
Potential Use

Sarcoidosis is a systemic granulomatous disease of unknown etiology and pathogenesis with a heterogeneous clinical presentation. In the appropriate clinical and radiological context and with the exclusion of other diagnoses, the disease is characterized by the pathological presence of non-caseating epithelioid cell granulomas. Sarcoidosis is postulated to be a multifactorial disease caused by chronic antigenic stimulation. The immunopathogenesis of sarcoidosis encompasses a complex interaction between the host, genetic factors and postulated environmental and infectious triggers, which result in granuloma development.The exact pathogenesis of the disease has yet to be elucidated, but some of the inflammatory pathways that play a key role in disease progression and outcomes are becoming apparent, and these may form the logical basis for selecting potential biomarkers.Biomarkers are biological molecules that are altered pathologically. To date, there exists no single reliable biomarker for the evaluation of sarcoidosis, either diagnostically or prognostically but new candidates are emerging. A diagnosis of sarcoidosis ideally requires a biopsy confirming non-caseating granulomas, but the likelihood of progression that requires intervention remains unpredictable. These challenging aspects could be potentially resolved by incorporating biomarkers into clinical practice for both diagnosis and monitoring disease activity.This review outlines the current knowledge on sarcoidosis with an emphasis on pulmonary sarcoidosis, and delineates the understanding surrounding the implication of biomarkers for the clinical evaluation of sarcoidosis.

scholarly journals Aggregation of population‐based genetic variation over protein domain homologues and its potential use in genetic diagnostics

2017 ◽  
Vol 38 (11) ◽  
pp. 1454-1463 ◽  
Author(s):  
Laurens Wiel ◽  
Hanka Venselaar ◽  
Joris A. Veltman ◽  
Gert Vriend ◽  
Christian Gilissen
Keyword(s):  
Genetic Variation ◽  
Population Based ◽  
Protein Domain ◽  
Genetic Diagnostics ◽  
Potential Use

scholarly journals Induced Expression of Sarcotoxin IA Enhanced Host Resistance Against Both Bacterial and Fungal Pathogens in Transgenic Tobacco

2000 ◽  
Vol 13 (8) ◽  
pp. 860-868 ◽  
Author(s):  
Ichiro Mitsuhara ◽  
Hiroki Matsufuru ◽  
Masahiro Ohshima ◽  
Hisatoshi Kaku ◽  
Yuki Nakajima ◽  
...  
Keyword(s):  
Fungal Infection ◽  
Transgenic Tobacco ◽  
Pseudomonas Syringae ◽  
Host Resistance ◽  
Fungal Pathogens ◽  
Erwinia Carotovora ◽  
Induced Expression ◽  
Sarcotoxin Ia ◽  
Resistance To Infection

We demonstrate here that induced expression of sarcotoxin IA, a bactericidal peptide from Sarcophaga peregrina, enhanced the resistance of transgenic tobacco plants to both bacterial and fungal pathogens. The peptide was produced with a modified PR1a promoter, which is further activated by salicylic acid treatment and necrotic lesion formation by pathogen infection. Host resistance to infection of bacteria Erwinia carotovora subsp. carotovora and Pseudomonas syringae pv. tabaci was shown to be dependent on the amounts of sarcotoxin IA expressed. Since we found antifungal activity of the peptide in vitro, transgenic seedlings were also inoculated with fungal pathogens Rhizoctonia solani and Pythium aphanidermatum. Transgenic plants expressing higher levels of sarcotoxin were able to withstand fungal infection and remained healthy even after 4 weeks, while control plants were dead by fungal infection after 2 weeks.

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