Bozena Morawski, PhDc, MPH
Nominated From: University of Minnesota
Research Site: Uganda
Research Area: HIV/AIDS; Parasites; Cryptococcal Meningitis
Primary Mentor: Dr. David Boulware
HIV and tropical co-infections: Does helminth co-infection alter the host immune response to cryptococcal meningitis, worsening disease severity?
Cryptococcal meningitis, caused by the fungi Cryptococcus neoformans and C. gattii, is the most common cause of adult meningitis in Africa, and causes 20-25% of HIV-related mortality in sub-Saharan Africa. Higher cerebrospinal fluid (CSF) fungal burden at diagnosis and slower rate of clearance of cryptococcal fungus from CSF have been independently associated with higher rates of mortality. Host response to the intracellular pathogen Cryptococcus is predominantly mediated by pro-inflammatory T-helper cell type 1 (Th1) immune responses, such as interferon gamma (IFN-γ). Impaired inflammatory response to Cryptococcus is associated with higher fungal burden and slower rates of clearance from the CSF.
In sub-Saharan Africa, intestinal helminth infections are also highly prevalent, and estimates place HIV and helminth co-infection at 10 to over 50%. These organisms provoke a type 2 T-helper cell (Th2) immune response, which is classically marked by elevated concentrations of IL-4, IL-5, IL-9 and IL-13.6 Helminths induce immune responses via multiple mechanisms. First, larval and adult helminths migrate through the intestines and other tissues, triggering cytokine alarmins that activate innate lymphoid cells toward a Th2 type adaptive immune response. Second, adult helminths reside in gut tissues, where they may activate Th2 effector cells and T regulatory cells. Furthermore, helminths release excretory/secretory products that inhibit the capacity of dendritic cells to facilitate T helper type 1 (Th1) cell differentiation.7 The cumulative effects of these exposures are powerful, and the systemic immune Th2 responses may promote disease progression and severity for intracellular organisms requiring a protective Th1 response (e.g. Cryptococcus or tuberculosis).
In the healthy individual – or people living with HIV – these potent immune responses may beneficially dampen inflammatory Th1 immune responses. However, in immunocompromised persons with systemic fungal infection, a concurrent helminth infection may in fact encourage an insufficient or inappropriate Th1 response, resulting in increased fungal burden, reduced innate ability to clear infection, and directly contribute to mortality and morbidity.
1. Determine prevalence and burden of 5 soil-transmitted helminth species in a tropical low-resource hospitalized population diagnosed with meningitis, using highly sensitive and specific quantitative PCR (qPCR).
2. Determine if among persons with cryptococcal meningitis, the quantitative burden of Cryptococcus (CFU/mL CSF) is greater in those with helminth co-infection compared to those without helminths.
3. Determine if the rate of Cryptococcus clearance from the CSF over the first 14 days of induction antifungal therapy is slower among persons with helminth infection(s) versus without helminths.
The interaction between Cryptococcus and helminth infection, as mediated by the helminth induced Th2 type immune response, has not been previously examined in people living with HIV. However, there is evidence to suggest that immunocompromised persons with strong Th2 type response cytokine expression are more likely to contract other infections, including cryptococcal meningitis. There is also evidence that infection with Th2 type immune response-inducing helminths down-regulates Th1 type responses in CSF as well as serum/plasma.
Should helminth infection influence host response to cryptococcal infection, affordable and effective antihelminthic treatments are readily available. Given the poor outcomes associated with cryptococcal meningitis in low resource settings, the high likelihood of helminth co-infection, and the potential influence of helminth infection on host response to Cryptococcus, evidence from this research has the potential to improve patient outcomes in these settings