Researchers at the Virginia Bioinformatics Institute’s Center for Modeling Immunity to Enteric Pathogens have completed a comprehensive study on gene networks that regulate immune system responses to H. pylori, a gut-dwelling bacterium carried by half the world’s population.
Recently published in the open access journal PLOS ONE, the discovery explains how the expression of certain genes changes in infection-fighting cells known as macrophages — information that could lead to early detection or prevention of stomach disorders.
Researchers at the center, a $12 million National Institute of Allergy and Infectious Diseases of the National Institutes of Health-funded resource, say the discoveries may lead to more accurate, personalized diagnoses about the threats posed by certain bacteria, and provide clues about how to understand and validate H. pylori’s health benefits.
Though H. pylori is most famously associated with peptic ulcers and stomach cancer, its effect on people varies widely depending on the individual. In many cases it even seems to benefit its carriers, contributing to lower instances of obesity and asthma.
Center for Modeling Immunity to Enteric Pathogens researchers are studying how the response of gastric immune cells to the infection affects health outcomes in people who carry this bacterium.
To understand how immune cells known as macrophages respond to H. pylori, the researchers sequenced RNA and identified a set of more than a 1,000 differentially expressed genes at six different periods in the hours following infection.
“With this big data set we were able to see how clusters of innate immune response genes shift during infection,” said Casandra Philipson, a Nutritional Immunology and Molecular Medicine Laboratory alumna and the scientific director of BioTherapeutics. “The temporal behavior of these newly identified gene modules becomes central for determining the impact of H. pylori on the host response. For instance, computational simulations predict that early onset genes control a key checkpoint, namely NLRX1, to balance microbial burden.”
The researchers discovered that H. pylori infection is suppressing members in a family of regulatory NOD-like receptors that play key roles in regulating innate immune response.
Suppression of regulatory molecules, such as NLRX1 and NLRC3, has been linked to several chronic inflammatory diseases including chronic obstructive pulmonary disease and inflammatory bowel disease. Down-regulation of these molecules impairs the ability for a host to control the balance between host tolerance and disease during infection.
The researchers discovered that NLRX1 might be facilitating the peaceful cooperation between H. pylori and its human host. Loss of NLRX1 significantly reduces H. pylori colonization and results in more hostile immune responses against the bacterium.
Additionally, the researchers characterize for the first time three sequential host response waves to H. pylori infection and use computational simulations as predicting mechanisms to understand what regulates host-microbial interactions.
The main computational hypothesis is that cell-signaling proteins known as cytokines control the dynamic behavior of NLRX1 in the early response wave. This is another novel finding of the study that remains to be validated in upcoming experiments.
“Like many other bacteria that have colonized the human gut for centuries, H. pylori exerts a positive impact on its hosts when managed at a certain level by their immune systems,” said Raquel Hontecillas, the co-director of the Nutritional Immunology and Molecular Medicine Laboratory. “Our findings about NLRX1 may reveal how this same equilibrium is maintained between humans and many other members of the gut microbiota.”
A multiyear undertaking, the entire research process — from initial genetic sequencing to data analysis, model development to lab tests — was carried out by a diverse team of experts within the Virginia Bioinformatics Institute.
“Big data analytics, immunology, computational biology: all of these methods make an important contribution toward answering the big questions of human health,” said Josep Bassaganya-Riera, director of the Nutritional Immunology and Molecular Medicine Laboratory. “MIEP’s embrace of team science allows all of that expertise to live under one roof and be applied toward creating computational models of massively interacting systems such as immune responses to infection.”