# PpiA, a multitasking mycobacterial virulence protein

> **NIH NIH R21** · JOHNS HOPKINS UNIVERSITY · 2020 · $204,688

## Abstract

PROJECT SUMMARY
With 10.4 million incident cases and 1.7 million deaths reported in 2016, tuberculosis (TB) continues to remain
one of the world's deadliest communicable diseases, and constitutes a significant burden on resource-limited
countries. An estimated 13% of new TB cases are also known to be HIV-positive. The causative agent,
Mycobacterium tuberculosis (MTB), persists within host macrophages, where it uses a plethora of complex
strategies to alter host immune responses in order to facilitate its long-term survival. HIV and MTB appear to
potentiate one another, accelerating the deterioration of host immune functions. The continued search for
bacterially secreted protein virulence factors that gain access to macrophages and modulate immune
responses has overlooked `moonlighting or multitasking' MTB proteins that have normal cellular functions
within the pathogen, but serve as virulence factors once secreted. Our recent studies indicate that PpiA, a
cyclophilin-like peptidyl-prolyl isomerase secreted by MTB, functions as a moonlighting protein that alters host
immune responses in vitro and in vivo. Using gain-of function and loss-of-function PpiA mutants of MTB, we
found that excess PpiA secreted by intracellular MTB reduced pro-inflammatory cytokine responses in vitro,
and led to increased bacterial burden and disease severity in a mouse model of TB, associated with
suppression of pro-inflammatory cytokine response. PpiA therefore acts as a bacterial virulence factor which
inhibits key intracellular host responses required for pathogen control. PpiA is also a human cyclophilin
analogue displaying close structural similarity, strongly suggesting that it could be deployed by MTB as an
effector mimic against the host cyclophilins, particularly during MTB/HIV co-infection, thus protecting HIV cDNA
from recognition by cGAS, and hence from subsequent antiviral Type I IFN response. Further contribution
could also come from its ability to bind IFITM1, an anti-viral protein produced in response to HIV infection. PpiA
produced by MTB could therefore significantly alter the host response and outcome of MTB mono-infection and
MTB/ HIV co-infection, suggesting a molecular basis for the well-known synergy between the pathogens.
Identifying host binding partners of PpiA, and evaluating its functional role during MTB infection and MTB/HIV
co-infection will therefore facilitate the recognition of novel therapeutic targets. Our aims therefore are to
identify macrophage host binding partner(s) for MTB PpiA (Aim 1), and to evaluate the role of PpiA and its
binding proteins in modulating host immune responses in vitro to MTB mono-infection and MTB/HIV co-
infection (Aim 2).

## Key facts

- **NIH application ID:** 9828763
- **Project number:** 5R21AI143610-02
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** WILLIAM Ramses BISHAI
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $204,688
- **Award type:** 5
- **Project period:** 2018-12-01 → 2020-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9828763

## Citation

> US National Institutes of Health, RePORTER application 9828763, PpiA, a multitasking mycobacterial virulence protein (5R21AI143610-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9828763. Licensed CC0.

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