Pneumocystis (PC) pneumonia remains a serious complication of HIV infection and other immunocompromised states. Recent ICD9 data show that since 2008 there are consistently 14-15,000 hospitalizations per year with an average cost of close to $1B per annum in the US alone. Moreover treatment for PCP has not changed in 20 years and there is concern of anti-microbial resistance and drug:drug interactions with TMP-SMX (the frontline therapy for PCP). We have shown that passive immunization with polyclonal antibodies or monoclonal antibodies or immmunoadhesins to surface antigens reduce the severity of PCP as ameliorate immune reconstitution syndrome. To date most of these therapies have been directed against the ascus form of the organism which is the environmental form. However RNAs-seq analyses shows that the troph is the replicative form and these data now open up to new avenues for therapeutics and diagnostics. First targeting antigens expressed on the surface of the trophozoite (and perhaps on the ascus as well) with therapeutic immunization or antibodies should abort the infection. Secondly as the trophozoite is the replicative form of infection a trophozoite- specific molecular diagnostic would improve sensitivity of clinical diagnosis which currently is still based on subjective histology. We will test these two hypotheses with the following specific aims:
Specific Aim 1. Determine the immunogenicity and efficacy of a dual life cycle vaccine for PCP.
Specific Aim 2. Determine the efficacy of dual life cycle antibodies to treat PCP and immune reconstitution syndrome (IRIS).
Specific Aim 3. Determine the positive predictive value of a troph specific molecular diagnostic compared to current methodology. The above aims will advance therapeutic and diagnostic options to reduce the morbidity and mortality of PJP.
Pneumocystis remains a significant cause of pneumonia with a high death rate in the US among HIV+ patients well as in other immunocompromised hosts. The estimated annual costs of PJP approximate $1B annually in the US. This grant will identify novel targets to improve treatment outcomes as well as improve diagnostics for this pneumonia in patients lacking CD4+ T-cell immunity such as advanced AIDS.
