Neuronal pathogenesis: acute and post-acute implications of viruses

National Institute Of Allergy And Infectious Diseases

Investigators

Abstract

Herpes simplex virus type 1 (HSV-1) is a highly adapted virus in humans, causing infections in the orofacial area and establishing lifelong latency in neuronal tissues like the trigeminal ganglion. When immune cells become exhausted, often following illness recovery, latent HSV-1 can reactivate, infecting neurons, triggering innate immune responses, and causing neuronal death. Frequent reactivations lead to neuroinflammation, amyloid beta accumulation, and neuronal loss, potentially resulting in chronic diseases such as Alzheimer's. To prevent both acute and chronic damage from HSV-1, the immune system must effectively clear the virus while protecting neuronal tissue. Understanding the molecular mechanisms modulating these antiviral immune responses may reveal new strategies to treat viral encephalitis and reduce neural harm. Our prior research demonstrated that mTORC2, a host multiprotein complex, promotes cell survival during viral stress via the mTORC2-Akt-FoxO3a pathway, which inactivates the proapoptotic FoxO3a. However, this pathway does not fully explain immune activation. Our recent findings add detail to this pathway, exploring how different Akt isoforms contribute to the specificity of the mTORC2-Akt-FoxO3a axis. We found that mice lacking either Akt1 or Akt2 had notably different immune profiles. Notably, Akt2 uniquely regulated cytokine production, which is key to immune coordination, and Akt2 also caused FoxO3a inactivation. These roles of Akt2 were not compensated by Akt1, indicating each isoform has distinct, non-overlapping functions in immune regulation during virus infection. These insights suggest that precisely modulating individual Akt isoforms could help balance immune response and minimize neuronal damage while maintaining viral control [Suryawanshi et. al. 2025a]. Since mTORC2 activates both Akt1 and Akt2, our next step is to understand the molecular switch that determines whether mTORC2 activates Akt1 (immune activation and cell death) or Akt2 (immune suppression and cell survival). Our subsequent research focused on innate immune evasion by respiratory viruses, specifically how the SARS-CoV-2 macrodomain (Mac1) helps virus to avoid immune activation. Macrodomains are found in viruses like alphaviruses, hepatitis E, and many betacoronaviruses. Mac1 enzyme inhibits ADP-ribosylation by PARP proteins, a process vital for antiviral interferon responses. Our studies show that inhibiting Mac1 with the novel AVI-4206 compound boosts the immune response and decreases viral replication and disease severity in human lung organoids and transgenic mice models. This pharmacological approach validates Mac1 as a drug target and could be applicable to other viruses with macrodomains that suppress host immunity [Suryawanshi et. al. 2025b]. Similarly, we developed a new series of small-molecule inhibitors based on a dihydrouracil core that target viral main proteases (Mpro). Leading compounds, like AVI-4773, significantly reduce viral titers after a few doses, and efficiently reach key tissues, including the brain, in animal models. These compounds act against SARS-CoV-2 and common cold coronaviruses, work synergistically with existing antivirals like molnupiravir, and can inhibit strains resistant to some clinical protease inhibitors [Detomasi et. al. 2025]. These findings point to new viral enzyme inhibitors as promising treatments for respiratory infections, especially as resistance to preexisting drugs rises. In addition to studying innate immunity in respiratory and neurological virus infections, we examined how cell signaling pathways support regenerating lung tissue damaged by Influenza A and coronaviruses. Our research identified Desert hedgehog (Dhh) signaling, produced by rare neuroendocrine epithelial cells, as a crucial factor in tissue repair after injury. When damage occurs from viral infection, Dhh is secreted, activating nearby mesenchymal cells to trigger regenerative and protective responses. This amplifies signals from a few neuroendocrine cells and initiates widespread tissue repair mechanisms. We also show that Dhh-driven epithelial-mesenchymal feedback is not limited to airways. In the pancreas, a similar pathway protects insulin-producing islets, relevant for diabetes treatment. Blocking Hedgehog signaling increases diabetes risk, while small molecules that enhance this pathway promote recovery from chemical or viral injuries. Thus, targeting Dhh signaling could offer therapeutic strategies to improve regeneration of neuroendocrine and other tissues after respiratory infections, opening new possibilities for treating both acute and chronic lung diseases [Kong et. al. 2025].