Huang, A. P. | Search bioRxiv

bioRxiv2022

Activation of a bacterial flow sensor by hypochlorous acid from stimulated neutrophils

Neutrophils kill bacteria by producing an array of lethal molecules, including hypochlorous acid (HOCl). The extent to which pathogens detect HOCl from neutrophils and defend themselves has not been understood. We report that the opportunistic pathogen Pseudomonas aeruginosa responds to activated neutrophils by upregulating the flow regulated operon (Fro), which was previously shown to be activated by fluid flow. We found that fro is upregulated in a mouse infection model where neutrophil influx occurs. This upregulation is induced in vitro by HOCl and its secondary product taurine chloramine but not by other neutrophil defense factors including LL-37, histones, or H2O2. HOCl induces the FroR-dependent upregulation of methionine sulfoxide reductases that relieve otherwise lethal oxidative stress. Fro expression is regulated by FroR's anti-sigma factor FroI, which contains the highest density of methionines and cysteines of all anti-sigma factors. The second-order rate constants of HOCl are highest with these residues, raising the possibility that the activation of fro could involve oxidation of FroI. These findings suggest a model in which flow transports oxidizing molecules that activate the fro operon, establishing an early warning system for P. aeruginosa that improves its survival against host immune defenses and persistence during infection.

microbiology↗

bioRxiv2021

Comparing Expression of OAS-RNaseL Pathway-Related Genes in SARS-CoV-2 and Similar Viruses

The COVID-19 pandemic, caused by the virus SARS-CoV-2, has been a major public health emergency and has caused millions of deaths worldwide to date. Due to the novel nature of the virus, efforts across the world are underway to better understand the molecular pathogenesis of SARS-CoV-2 and how it interacts with host immune responses. One important branch of the innate immune response, the interferon system, triggers the expression of many effector mechanisms known to be powerful antagonists against many pathogenic viruses. One such interferon stimulated mechanism is the OAS-RNaseL pathway, which is known to trigger the degradation of viral RNA in infected host cells. Our study seeks to utilize publicly available transcriptomic data to analyze the host cell OAS-RNaseL pathway to SARS-CoV-2 infection. We hoped to gain an understanding of the importance of the pathway in controlling SARS-CoV-2 infection and whether or not the pathway could be exploited therapeutically. Our findings demonstrated that upregulation of OAS-RNaseL pathway genes in response to SARS-CoV-2 infection varies based on cell type and appeared to correlate with ACE2 receptor expression. Pathway responses to other viruses like SARS-CoV and MERS-CoV were found to parallel those to SARS-CoV-2, suggesting common response patterns by the pathway to these viruses. Overall, these results demonstrate that the OAS-RNaseL pathway could contribute to control of SARS-CoV-2 infection. Further studies on various mechanistic actions by the pathway would need to be conducted to fully understand its role in host defense and therapy.

immunology↗