Mapping of the IgM and IgG antibody responses to Talaromyces marneffei infection in mice and humans - Deciphering acute from reactivated or latent infections

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Abstract Talaromycosis is an invasive mycosis caused by the dimorphic fungus Talaromyces marneffei (Tm) endemic in Southeast Asia. Infection kills one in three infected people with a compromised immune system, and is the leading causes of HIV-associated death in the endemic region. Current diagnostics can only identify the fungus in late stage infection. We know infection can reactivate up to 7 years from exposure in returning travelers, but we lack an antibody test to determine who has been infected and who has a primary versus a reactivated infection. We and other have documented a 30-70% increase in cases during the rainy humid months in multiple countries. Our epidemiology studies suggest that this remarkable seasonality is due to acute exposure leading to acute primary infections rather than alterations in host factors. Our human cohorts, including the IVAP clinical trial, have shown that patients who present with an acute pulmonary syndrome have a shorter duration of illness and rapidly progressive fatality. Our central hypothesis is that the acute pulmonary form of infection has a more virulent pathogenesis than the reactivated form, and host IgM and IgG patterns can differentiate between these forms. We propose two related but independent aims to test this hypothesis. AIM 1. To validate the novel anti-Mp1p IgM and IgG enzyme immunoassay (EIA) and to delineate the impact of acute primary infection on patient outcomes. Here, we will leverage the IVAP trial biorepository with longitudinal plasma samples (6 timepoints collected over 24 weeks) from 440 culture-confirmed talaromycosis patients to map the IgM and IgG responses in humans, identify the IgM/IgG serological pattern associated with acute infection, and determine the impact of acute primary infection on patient outcomes. AIM 2. To develop a novel murine pulmonary model to decipher the host anti-Tm antibody responses to primary versus reactivated infection. Here, we will develop a novel pulmonary model using non-invasive oropharyngeal aspiration and low infection inoculum to mimic natural human infection. We will develop an acute primary infection model in CD4-depleted mice and develop chronic infection in immunocompetent mice, followed by CD4 depletion to induce a reactivated infection model. Our goal is to understand how a mammalian antibody response should differ between primary versus reactivated infection and use the mouse antibody data to strengthen the interpretation of antibody responses in humans. Impact. Our studies aim to establish a serological diagnosis for talaromycosis which has the potential to differentiate acute from reactivated infection and expand our knowledge of disease spectrum. The new murine pulmonary model will facilitate new research into the host immune response to Tm infection. The antibody test will enable population-based seroprevalence studies to advance our understanding of disease burden, geographic risk, latency, and risk populations. This knowledge will inform both disease management at the individual level and prevention strategies at the population level.