# The role of ACE2 in Influenza viral infection mediated immune compromise and subsequent bacterial lung infection

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2021 · $578,890

## Abstract

Project Summary
Overall goal of this application is to advance our understanding of ACE2 biology in the lung, to explore a
novel link between ACE2 activity and the interferon-γ-mediated compromised innate immunity in IAV and
subsequent bacterial lung infection, and to lay the groundwork for a new strategy to prevent and treat lethal
IAV-bacterial coinfection by manipulating ACE2 activity. Infection with secondary bacterial pathogens is the
primary cause of excess mortality during influenza A virus (IAV) outbreaks. Novel therapies that modulate host
immunity are urgently needed. Moreover, compelling evidence indicates that the immune defects caused by IAV
infection are responsible for the severe secondary bacterial lung infection. These include impaired neutrophil influx
due to sustained desensitization and the induction of an immune-suppressive state of the lung. The renin-angiotensin
system (RAS) is constitutively activated to maintain blood pressure and to mount a host defense to invading
microbes. However, overactive RAS facilitates exacerbated inflammatory response, while repressive RAS curbs host
defense. Thus, regulation of optimal RAS signaling may represent a novel therapeutic strategy in a bacterial lung
infection. Angiotensin-converting enzyme 2 (ACE2) is a potent negative regulator of the RAS activation. Our
preliminary studies in a mouse model of IAV-bacterial coinfection indicate that pulmonary ACE2 is dynamically
regulated during IAV infection and peaked around 6 dpi. Interestingly, the IAV induced interferon- γ induces ACE2
expression. We also find that the elevated pulmonary ACE2 activity at the time of secondary bacterial infection
mitigates neutrophilic inflammation and increases the severity of the secondary bacterial infection. The observation
raises the possibility that the IAV infection induced ACE2 activity, partially by interferon- γ, predispose the mice to
secondary bacterial lung infection by attenuating neutrophilic inflammatory response. Our overall hypothesis is
that is that ACE2 plays a pivotal role in the IAV induced-IFN- γ mediated immune compromise, thus contributes
to the pathogenesis of secondary bacterial lung infection post IAV, and that optimal strategy to manipulate
active ACE2 will improve the outcome of IAV-bacterial coinfection. We propose the following aims:
Aim1. To investigate the role and mechanism of IFN- γ induced pulmonary ACE2 in IAV-bacterial coinfection.
manipulate active ACE2 will improve the outcome of IAV-bacterial coinfection. Aim2. To elucidate the mechanisms
through which pulmonary ACE2 modulates neutrophil influx in IAV-bacterial coinfection. Aim3. To evaluate the
preventive and interventional strategies to IAV-bacteria co-infection by monitoring serum and manipulating
pulmonary ACE2 activity.
These studies will make a significant conceptual advance and pre-clinical insight by defining the role and
therapeutic potential of ACE2 in IAV-bacterial lung disease.

## Key facts

- **NIH application ID:** 10165489
- **Project number:** 5R01AI148446-02
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Hongpeng Jia
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $578,890
- **Award type:** 5
- **Project period:** 2020-05-15 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10165489

## Citation

> US National Institutes of Health, RePORTER application 10165489, The role of ACE2 in Influenza viral infection mediated immune compromise and subsequent bacterial lung infection (5R01AI148446-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10165489. Licensed CC0.

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