# Regulation of host innate and adaptive immunity by bacterial type III effectors

> **NIH NIH R01** · DARTMOUTH COLLEGE · 2021 · $361,861

## Abstract

Type III secretion (T3S) systems are used by bacterial pathogens to translocate effectors into infected host
cells to promote virulence. T3S can also trigger compensatory innate immune responses that can protect the
infected host. For example, T3S can trigger inflammasome assembly in infected host cells, resulting in cell
death and secretion of cytokines. Virulent pathogens must therefore inhibit protective compensatory host
immune responses triggered by T3S. The long-term objective of this project is to understand how a T3S
system in the bacterial pathogen Yersinia initially triggers and subsequently inhibits host inflammasomes. A
possible link between a human genetic autoinflammatory disease and resistance to Yersinia infection is also
explored. The T3S effector YopE is a GTPase-activation protein (GAP) that promotes Yersinia virulence by
deactivating RhoA to inhibit phagocytosis. YopE RhoA GAP activity was recently shown to trigger the pyrin
inflammasome in macrophages. Bacterial toxins that covalently inactivate RhoA are known to trigger the pryin
inflammasome, via a regulatory mechanism that uses the kinase PRK. Specifically, active RhoA positively
regulates PRK by allosteric interaction and PRK negatively controls pyrin by phosphorylation. Triggering of the
pryin inflammasome by the YopE GAP is unexpected because published data indicated that this response
required covalent inactivation of RhoA. It is unknown if YopE triggers the pyrin inflammasome by the same
mechanism as toxins that covalently inactivate RhoA, and it is unclear if other bacterial RhoA GAPs induce this
response. Aim 1 will test the hypothesis that YopE, other bacterial GAPs, and toxins that covalently modify
RhoA, trigger the pryin inflammasome by a conserved allosteric mechanism of PRK inactivation. The T3S
effector YopM promotes Yersinia virulence by inhibiting inflammasomes. It has recently been discovered that
YopM inhibits pyrin, allowing Yersinia to bypass YopE-triggered inflammasomes. Mechanistically, YopM
hijacks PRK to maintain pyrin in a phosphorylated and inactive state. Published data obtained using knock out
mouse lines in Yersinia infection assays suggest that YopM targets inflammatory monocytes to promote
Yersinia virulence. Aim 2 will test the hypothesis that Yersinia virulence requires YopM to inhibit activation of
pyrin in inflammatory monocytes. Codon changes in the gene Mefv, which encodes pyrin, are responsible for
the human autoinflammatory disease Familial Mediterranean Fever (FMF). It has been suggested that the
high carrier frequency of FMF in Mediterranean and Middle Eastern populations has resulted from a selective
advantage in resistance to an unknown infection. Aim 3 will test the hypothesis that FMF pyrin variants, which
trigger constitutive inflammasome activation, provide host resistance to Yersinia pestis infection.

## Key facts

- **NIH application ID:** 10137878
- **Project number:** 5R01AI099222-10
- **Recipient organization:** DARTMOUTH COLLEGE
- **Principal Investigator:** James B Bliska
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $361,861
- **Award type:** 5
- **Project period:** 2012-05-01 → 2022-09-19

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10137878

## Citation

> US National Institutes of Health, RePORTER application 10137878, Regulation of host innate and adaptive immunity by bacterial type III effectors (5R01AI099222-10). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10137878. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*