# Anti-inflammatory bioactive lipids exacerbating Staphylococcus aureus infection post influenza

> **NIH NIH R21** · TEMPLE UNIV OF THE COMMONWEALTH · 2020 · $198,125

## Abstract

PROJECT SUMMARY/ABSTRACT
Secondary bacterial infection following influenza (super-infection) is a serious clinical complication that often
leads to pneumonia and death in patients. In most infection models, a single species or organism of microbial
pathogen is used to induce an insult or disease in the host. However, humans are constantly exposed to a
multitude of microbial pathogens simultaneously. The resulting signaling crosstalk in the immune system has
largely been overlooked. An unbiased, holistic systems biology approach, therefore, is required to decipher the
molecular interactions between the mammalian host, influenza virus and the bacterial pathogen. We have
previously used this approach to study the immune response during single (influenza or Staphylococcus
aureus) and super-infection (influenza/S. aureus). We conducted transcriptional and lipidomic analyses in
samples from a mouse super-infection model. We focused our lipidomic analysis on eicosanoids because they
are signaling molecules that play critical roles in the induction and resolution of inflammation. During super-
infection, when compared to single infections, anti-inflammatory CYP450 metabolites, natural ligands for the
nuclear receptor PPARa, were produced at a significantly higher level. We hypothesize that these lipids
normally promote the physiological resolution of inflammation. However, during super-infection, CYP450
metabolites are produced at a pathological level leading to an over-activation of PPARa in innate immune
cells. The activation of PPARa, in turn, compromises the anti-bacterial function of neutrophils and monocytes.
The persistence of bacteria provides immune signals that amplify a feedforward loop to recruit more immune
cells, thus contributing to tissue damage and eventual mortality. We will take the following approaches during
single and super-infection to investigate the effects of the bioactive lipids-PPARa axis on the innate immune
function and signaling. First, we will identify the transcriptional networks of infiltrating neutrophils and
monocytes, the predominant cell types recruited to clear bacterial pathogens during S. aureus infection with or
without prior influenza. We will further characterize the anti-bacterial function of the neutrophils and monocytes
in the presence of genetic (wildtype C57/Bl6 versus Ppara–/– mice) and chemical (agonists and inhibitors
against PPARa) perturbations. Using shRNA and gene editing, we will determine the genetic interactors of
PPARa which collaborate to alter the transcriptional response. Second, we will determine the lipidomic
landscape during the late phase of super-infection when bacterial persistence triggers further infiltration of
immune cells. We will investigate whether using chemical inhibitors against PPARa and the eicosanoid
metabolic pathways can alleviate the increased morbidity and mortality phenotype during super-infection.
Using transcriptional and lipidomic approaches to study the bioactive l...

## Key facts

- **NIH application ID:** 9979757
- **Project number:** 5R21AI142278-02
- **Recipient organization:** TEMPLE UNIV OF THE COMMONWEALTH
- **Principal Investigator:** Vincent Tam
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $198,125
- **Award type:** 5
- **Project period:** 2019-07-17 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9979757

## Citation

> US National Institutes of Health, RePORTER application 9979757, Anti-inflammatory bioactive lipids exacerbating Staphylococcus aureus infection post influenza (5R21AI142278-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9979757. Licensed CC0.

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