# Role reversal of MAVS in bacterial sepsis

> **NIH NIH R01** · BOSTON UNIVERSITY MEDICAL CAMPUS · 2022 · $482,381

## Abstract

Sepsis is a frequent and life-threatening complication of microbial infections. It is estimated that more than
750,000 annual cases of sepsis occur in the United States and mortality rates remain around 20-50% despite
recent advances of critical care support. In the current absence of FDA-approved pharmacologic compounds,
there remains an urgent need for a complete characterization of the underlying cellular and molecular
mechanisms of sepsis. The dysregulated host response is a prominent feature during the pathophysiology of
bacterial sepsis, but the delicate balance of its integrating molecular pathways appear not entirely clear.
Mitochondrial antiviral-signaling protein (MAVS) is an adaptor molecule in the outer mitochondrial membrane
and is highly expressed in professional phagocytes. MAVS is activated by the cytoplasmic RNA helicases, RIG-
I and MDA5, and confers protection against viral infections. Surprisingly, our preliminary findings suggest
deletion of MAVS or RIG-I/MDA5 in mice confers immense resistance to mortality and modulates phagocyte
transcriptomes, immunoproteasomes, extracellular traps, IL-6/IL-12 cytokines and blood coagulation during
polymicrobial bacterial sepsis. Bacterial RNAs are a viability-associated pathogen patterns (`vita-PAMPs')
sensed by the MAVS pathway in macrophages. Together, these findings suggest a detrimental role reversal of
MAVS during bacterial sepsis as opposed to protective MAVS pathway functions during infections with viruses.
To test our central hypothesis that MAVS signaling provides a lethal switch for obstructing favorable sepsis
outcomes, we will pursue 3 specific aims: (1) We will study the gene expression, activation mechanisms,
signaling events and functional roles of MAVS in professional phagocytes (macrophages, neutrophils) during
polymicrobial bacterial sepsis. For these studies, mice with total or conditional gene deletion of MAVS, or the
RIG-I/MDA5 sensors are available. MAVS-deficient human macrophages will be generated using CRISPR-Cas9.
(2) We will determine how MAVS-induced transcription factors promote gene expression of immunoproteasome
subunits, what the pleiotropic functions of the immunoproteasome are during bacterial sepsis, and how the
immunoproteasome shapes the proteomes and transcriptomes of macrophages. These studies will include using
triple-knockout mice for all three regulatory immunoproteasome subunits (PSMB8/9/10). (3) We will study how
the MAVS pathway amplifies the harmful molecular sequelae of bacterial sepsis focusing on phagocyte
extracellular traps (NETs/METs), IL-6/IL-12 cytokines, septic coagulopathy and immunosuppression; which all
contribute to tissue injury, organ dysfunction and sepsis lethality. In particular, we will consider a novel role of
the immunoproteasome in subcellular protein degradation for facilitating extracellular trap formation. In summary,
elucidating the previously unsuspected involvement of the MAVS pathway during bacterial infection will...

## Key facts

- **NIH application ID:** 10439602
- **Project number:** 5R01HL141513-05
- **Recipient organization:** BOSTON UNIVERSITY MEDICAL CAMPUS
- **Principal Investigator:** Markus Bosmann
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $482,381
- **Award type:** 5
- **Project period:** 2018-08-15 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10439602

## Citation

> US National Institutes of Health, RePORTER application 10439602, Role reversal of MAVS in bacterial sepsis (5R01HL141513-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10439602. Licensed CC0.

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