ELUCIDATING THE MECHANISM OF MICROGLIAL NEUROPROTECTION DURING H5N1 NEUROPATHOGENESIS - PROJECT SUMMARY HIG…

Assistance award details

Assistance award identifier

ASST_NON_F31AI203053_075

FAIN

F31AI203053

Recipient

UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION

Awarding agency

Department of Health and Human Services

Funding agency

Department of Health and Human Services

Assistance listing (CFDA)

93.855

Total obligated

$50,114

Period

Feb 13, 2027 – Feb 12, 2028

Fiscal year

2026

Place of performance state

PA

Source file

FY2026_All_Assistance_Full_20261006.zip

Description

ELUCIDATING THE MECHANISM OF MICROGLIAL NEUROPROTECTION DURING H5N1 NEUROPATHOGENESIS - PROJECT SUMMARY HIGHLY PATHOGENIC H5N1 AVIAN INFLUENZA VIRUS IS A RE-EMERGING ZOONOTIC PATHOGEN OF SIGNIFICANT PANDEMIC CONCERN. ALTHOUGH H5N1 IS CLASSICALLY CHARACTERIZED AS A RESPIRATORY VIRUS, RECENT H5N1 INFECTIONS IN MULTIPLE MAMMALIAN SPECIES HAVE LED TO THE INCIDENCE OF NEUROLOGICAL SIGNS, SUCH AS ATAXIA, PARALYSIS, AND SEIZURES. UPON PATHOLOGICAL AND HISTOCHEMICAL OBSERVATION, DIRECT INVASION OF H5N1 INTO THE BRAIN HAS BEEN SEEN, LEADING TO NEUROLOGICAL DISEASE. IN VITRO, H5N1 POSSESSES THE ABILITY TO REPLICATE IN A VARIETY OF NEURAL CELLS, SUCH AS NEURONS, ASTROCYTES, AND MICROGLIA. IN VIVO, IT APPEARS THAT NEURONS ARE MOST SUSCEPTIBLE TO H5N1 INFECTION, LEADING TO THE INDUCTION OF NEURONAL DEATH VIA APOPTOSIS OR NECROSIS. H5N1 NEURONAL INFECTION HAS BEEN ASSOCIATED WITH THE ACTIVATION OF MICROGLIA; HOWEVER, THE OUTCOME OF MICROGLIAL ACTIVATION DURING H5N1 NEURONAL INFECTION IS UNKNOWN. MICROGLIA ARE TISSUE-RESIDENT, YOLK SAC-DERIVED BRAIN MACROPHAGES, AND ARE CRUCIAL FOR MAINTAINING CENTRAL NERVOUS SYSTEM (CNS) HOMEOSTASIS VIA INNATE IMMUNE FUNCTIONS AND DIRECT NEURONAL INTERACTIONS. IMPORTANTLY, MICROGLIA HAVE BEEN SHOWN TO BE NECESSARY FOR INHIBITING THE NEURONAL REPLICATION OF SEVERAL NEUROTROPIC VIRUSES AND MEDIATING VIRAL CLEARANCE VIA SENSING OF EXTRACELLULAR PURINES. IN THIS PROPOSAL, WE WILL USE MICROGLIA-NEURON CO-CULTURES AND PHARMACEUTICALLY ABLATE MICROGLIA IN MICE TO ELUCIDATE THE ROLE OF MICROGLIA DURING H5N1 CNS INFECTION. WE HYPOTHESIZE THAT MICROGLIA ARE NECESSARY TO INHIBIT H5N1 CNS REPLICATION AND DISSEMINATION BY PURINERGIC-DEPENDENT PHAGOCYTOSIS OF INFECTED NEURONS, CONTROL OF INFLUENZA- INDUCED CELL DEATH, AND LIMITATION OF PERIPHERAL IMMUNE CELL RECRUITMENT. OUR PRELIMINARY RESULTS SHOW THAT H5N1 REPLICATION IN NEURONS IS IMPEDED IN THE PRESENCE OF MICROGLIA, BUT THE MECHANISM BY WHICH THIS OCCURS IS UNCLEAR. WE PROPOSE THAT THIS IS DEPENDENT ON M