Pneumocystis carinii (Pc) organisms are eukaryotic opportunistic pathogens that cause an oftentimes fatal pneumonia (PcP) in immunocompromised hosts, especially those with AIDS. Despite the progress made towards understanding the genetic structure of Pc, knowledge of its basic biology, including life cycle, transmission and epidemiology remains limited, resulting in reduced ability to clinically manage or prevent PcP. During the previous grant period, 2 genetically distinct Pc populations in a rat model PcP, """"""""prototype"""""""" and """"""""variant"""""""" and several sub-populations were defined. A cryopreserved catalogue of these different Pc populations has been established in the PIs laboratory and is a primary resource for the proposed studies. Recent studies of the epidemiology of human PcP have shown that patients with AIDS can also be infected with 2 different types of Pc, as well as a single type. Recurrent human Pc infections were caused by a previous Pc type or another type presumably acquired through the environment. Understanding of the reservoir for PC and the ability of hosts to transmit infection is of critical importance. Studies planned in the present proposal will exploit the rat model of PcP as a paradigm of human PcP using the characterized Pc population to: 1. Characterize the progression of infection and pathology of mixed and single Pc infections. Co-infections of prototype and variant Pc populations within a single rat lung are common, while co-infections of prototype-populations are rare. It is the PI's hypothesis that prototype-variant and single prototype infections are advantageous to organism survival while most prototype coinfections inhibit the progression of infection and aid the host response. In this Aim, the virulence of single and mixed infections will be assessed by growth rates; organism burden; mortality; and histopathology. Effects of the Pc infections on the host will be measured by humoral and cell-mediated functional assays. 2. Assess latency and transmission of mixed and single infections in immune competent and immunosuppressed hosts. The reservoir (s) of PC infection is not known, which is a critical issue in control of PcP. Some Pc populations have been observed to be more dominant among the rat colonies surveyed. A series of studies are planned to investigate the transmission of mixed and single Pc populations. The times of exposure needed to induce infection will be assessed; the latency period of Pc and ability to transmit the infection in immunocompetent hosts will be determined; and the role of host immune responses in latency and transmission will be evaluated. These studies will result in a clearer understanding of the biology leading to infection with Pc and will provide a rational basis for clinical management and therapeutic intervention.
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