Cryptococcal meningitis (CM) is an opportunistic fungal infection that primarily affects immunocompromised individuals, particularly those with HIV/AIDS. In resource-limited countries, patients often receive antifungal drug fluconazole monotherapy; however, long-term outcomes, even at high doses, are poor. In this episode, Neil Stone and colleagues observed treatment response in a cohort of patients with HIV-associated CM given fluconazole alone or in combination with flucytosine. Patients treated with fluconazole monotherapy had an increase in resistant subpopulations in the CSF; however, combination prevented expansion of resistant populations. Fluconazole-resistant strains had high rates of aneuploidy characterized predominant diploidy of drug efflux pump-containing chromosome 1. Together, these results support combination therapy as a successful strategy for suppressing heteroresistance.
Group A streptococcus (GAS) is a common cause of life-threating necrotizing fasciitis and myositis. Necrotizing disease is relatively rare; however, it has a high rate of mortality, and affected limbs must often be amputated. In this episode, James Musser and colleagues use transposon-directed insertion-site sequencing (TraDIS) to identify GAS genes required for the development of necrotizing myositis in a nonhuman primate model. In particular, several bacterial transporters were determined to be required for infection, and thereby represent potential therapeutic targets for this devastating disease.
Neurobiologist Carla Shatz, director of Stanford University Bio-X, has focused her research on how early brain circuits are transformed into adult connections during critical periods of development. Her work, which focuses on the development of the mammalian visual system, has relevance not only for treating disorders such as autism and schizophrenia, but also for understanding how the nervous and immune systems interact. This interview provides insights about what you can you learn from ski racing and how she got inspired to study neuroscience after her grandmother’s stroke.
Activity-dependent neuroprotective protein (ADNP) is essential for brain formation, and mutations in the ADNP-encoding gene have been linked to an autism-like syndrome in children that is characterized by developmental delay along with intellectual and social disabilities. An 8-amino acid motif derived from ADNP (referred to as NAP) has been shown to be neuroprotective, via enhancing dendritic spine formation, in mice lacking ADNP. In this episode, Illana Gozes and colleagues characterize Adnp+/- mice as a model of ANDP syndrome. Adnp+/- animals had reduced dendritic spine density, developmental delays, impaired vocalizations, and motor dysfunction along with memory and social impairment. Administration of NAP partially reversed behavior and developmental defects and increased dendritic spine density. The results of this study support further exploration of NAP administration for treatment of ADNP syndrome.
Graft-versus-host-disease (GVHD) is a life-threatening complication of allogeneic BM transplantation that affects skin, liver, and the gastrointestinal (GI) tract. GI involvement is associated with the most severe form of disease and outcomes for these patients are poor. Treatments for GVHD are limited; therefore, a better understanding of markers of GI involvement have potential to improve treatment. In this episode, James Ferrara and colleagues identify the Paneth cell protein regenerating islet-derived 3α (REG3α) as a biomarker that is upregulated in sera of patients with GI GVHD. Moreover, using murine models, the authors determined that REG3α, which has well-known antimicrobial function, promotes intestinal stem cell survival; thereby, protecting the intestinal barrier. Together, these results indicate that strategies to increase REG3α should be explored for limiting GI GVHD.