Mouse Model of a Human STAT4 Point Mutation That Predisposes to Disseminated Coccidiomycosis

Area of Science:

• Immunology
• Genetics
• Mycology

Background:

• Signal transducer and activator of transcription 4 (STAT4) is crucial for innate and adaptive immunity, particularly Th1 responses.
• Th1 responses are vital for controlling fungal infections, including coccidioidomycosis, a respiratory illness endemic to the southwestern US.
• Disseminated coccidioidomycosis can occur in individuals with compromised immune systems, sometimes due to unknown genetic factors.

Purpose of the Study:

• To investigate the role of a specific STAT4 genetic variant in the pathogenesis of disseminated coccidioidomycosis.
• To determine the functional consequences of this STAT4 variant on immune cell responses.
• To elucidate the mechanism by which STAT4 deficiency leads to susceptibility to fungal infection.

Main Methods:

• Genetic analysis of a family with disseminated coccidioidomycosis identified a heterozygous mutation in STAT4 (c.1877A>G).
• Generation and analysis of a STAT4 knockin mouse model heterozygous for the identified mutation.
• Assessment of T cell cytokine production (IFN-γ) and immune cell responses in vitro and in vivo following infection.

Main Results:

• The STAT4 mutation (Gly626) was associated with more severe experimental coccidioidomycosis in knockin mice compared to wild-type.
• Stat4 T cells from mutant mice showed impaired IFN-γ production upon stimulation.
• Mutant mice exhibited defective early IFN-γ and cytokine production in the lungs and reduced adaptive immune cell accumulation in lymph nodes post-infection.

Conclusions:

• Defective STAT4 function due to the c.1877A>G variant impairs early IFN-γ induction and adaptive immune responses.
• This immune deficiency prevents effective control of coccidioidomycosis, leading to disseminated disease in both mice and humans.
• STAT4 is essential for host defense against Coccidioides fungal infections.