Project Details
Description
Project Summary
Influenza A virus is a seasonal pathogen with the potential to unpredictably cause devastating pandemics.
Influenza has a broad tropism within the respiratory tract infecting many different subsets of epithelial cells.
These epithelial cells are the primary target of influenza infection and are responsible for amplifying and
spreading the infection. These cells are also critical sentinels detecting the virus and initiating antiviral immune
responses. It is difficult to determine early replication events because it is hard to label infected cells rapidly
after infection. Additionally, the virus spreads within the lung making it difficult to disentangle low replication
levels from new infections. To overcome these caveats, we used a single cycle reporter system that robustly
labels infected cells and is restricted to the first cell types infected. Our preliminary data demonstrate that cells
supporting different levels of virus replication express distinct sets of interferon-stimulated genes. These data
demonstrate that the antiviral response is tuned to level of replication. Using a sequential infection strategy
where the single cycle viruses express discrete fluorophores to specifically label primary and secondary
infected cells we have demonstrated that ciliated epithelial cells are specifically protected during the second
wave of virus replication. These data demonstrate that virus tropism is significantly shaped by innate immune
responses during virus dissemination. The objective of this research is to determine responses that inhibit
influenza virus replication and to determine how virus tropism is altered during innate immune responses in
vivo. Our central hypothesis is that cellular responses to infection become tailored to the stages of viral
replication and the round of infection which impacts overall viral replication levels and cellular tropism. Our
studies will address this hypothesis through use of a combination of reporter viruses that can determine the
degree, stage, and round of replication to elucidate fundamental antiviral processes in vivo. We will address
this hypothesis in two aims. Aim 1 will be to determine how varying levels of replication induce unique ISGs
and the role of the resulting effector proteins in the antiviral response. Aim 2 will focus on elucidating the
mechanisms of protection of epithelial cell subsets during virus spread. Results from this proposal will uncover
fundamental mechanisms in virus-host interactions and antiviral immunity.
Status | Active |
---|---|
Effective start/end date | 3/1/20 → 2/28/25 |
Funding
- National Institute of Allergy and Infectious Diseases: $498,044.00
- National Institute of Allergy and Infectious Diseases: $451,151.00
- National Institute of Allergy and Infectious Diseases: $501,278.00
- National Institute of Allergy and Infectious Diseases: $500,200.00
- National Institute of Allergy and Infectious Diseases: $501,278.00
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