Inter-individual variation in health and disease associated with pulmonary infectious agents

Abstract

Respiratory infectious diseases resulting from bacterial or viral pathogens such as Mycobacterium tuberculosis, Streptococcus pneumoniae, respiratory syncytial virus (RSV), or influenza, are major global public health concerns. Lower respiratory tract infections are leading causes of morbidity and mortality, only behind ischemic heart disease and stroke (GBD 2015 LRI Collaborators in Lancet Infect Dis 17(11):1133–1161, 2017). Developing countries are particularly impacted by these diseases. However, while many are infected with viruses such as RSV (> 90% of all individuals are infected by age 2), only sub-populations develop severe disease. Many factors may contribute to the inter-individual variation in response to respiratory infections, including gender, age, socioeconomic status, nutrition, and genetic background. Association studies with functional single nucleotide polymorphisms in biologically plausible gene candidates have been performed in human populations to provide insight to the molecular genetic contribution to pulmonary infections and disease severity. In vitro cell models and genome-wide association studies in animal models of genetic susceptibility to respiratory infections have also identified novel candidate susceptibility genes, some of which have also been found to contribute to disease susceptibility in human populations. Genetic background may also contribute to differential efficacy of vaccines against respiratory infections. Development of new genetic mouse models such as the collaborative cross and diversity outbred mice should provide additional insight to the mechanisms of genetic susceptibility to respiratory infections. Continued investigation of susceptibility factors should provide insight to novel strategies to prevent and treat disease that contributes to global morbidity and mortality attributed to respiratory infections.

Genetic influences on viral-induced cytokine responses in the lung

“…In challenges with IAV, this model replicates human blood transcriptional responses to infection and has identified several quantitative trait loci contributing to specific host responses. 171,172 Human association studies that have identified polymorphisms in biologically plausible gene candidates provide some insights into molecular genetic contribution to pulmonary infections and disease severity; however, the function of these SNPs needs to be further dissected, 173 as statistical association studies do not provide mechanisms, making it difficult to establish causality between a candidate genotype and a clinical phenotype. Understanding these mechanisms requires detailed biochemical and immunological studies.…”

Differential methylation as a mediator of COVID-19 susceptibility

“…It should be noted that this difference in individual susceptibility is actually not that unusual for infectious diseases, and thus not unique for COVID-19. The same is true for tuberculosis, malaria and the 'common' flu 11 . The underlying reason, however, is mostly disease-specific due to the fact that the biological pathways involved in the manifestation of the illness often differ.…”

The interplay between environmental exposures and COVID-19 risks in the health of children

“…Individual genetic susceptibility is likely to have a role in severity of disease after infection with SARS-CoV-2 [ 16 , 17 ] and may also influence viral infectivity and vaccine efficacy, as has been demonstrated for other viral infections [ 45 ]. Why a severe cytokine storm does not appear frequently in children remains a mystery, especially when this can occur in other childhood conditions.…”