# Dissecting Cell Death Pathways in Influenza A Virus Infection: Comparative Insights from Human Models

## TL;DR

This review compares how different human cell models respond to influenza by triggering cell death, aiming to improve understanding of the virus's effects and treatment strategies.

## Contribution

The paper provides a systematic comparison of programmed cell death in human-relevant influenza models, highlighting model-specific differences and translational gaps.

## Key findings

- Human models show distinct pathway activation and cell-type vulnerability compared to murine models.
- Bystander effects and spatial dynamics vary across experimental platforms.
- Gaps remain in comparative analyses across viral strains and model systems.

## Abstract

Influenza A virus remains a major global health threat, causing annual epidemics and occasional pandemics. Programmed cell death, including apoptosis, pyroptosis, and necroptosis, with emerging evidence for ferroptosis, plays a dual role in influenza pathogenesis, both limiting viral replication and contributing to immunopathology. Most mechanistic insights have been derived from murine genetic models, which have been invaluable for establishing causal roles of these pathways. However, murine models and cancer-derived cell lines differ significantly from human physiology. This review systematically compares influenza-induced programmed cell death across human-relevant platforms, including primary cells, immortalized non-cancerous lines, co-cultures, organoids, and precision-cut lung slices. The increasing complexity of these models reveals distinct aspects of pathway activation, bystander effects, cell-type vulnerability, and spatial dynamics. We highlight critical divergences between model systems, identify gaps in comparative analyses across viral strains and experimental platforms, and outline future directions leveraging advanced model systems, multi-omics, and functional genomics to enhance translational relevance and guide the development of host-directed therapies.