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Pneumocystis carinii is an opportunistic pathogen that causes infection almost exclusively within the alveolar spaces. The alveolar macrophage (AM) is the native immunoregulatory cell of the alveolar spaces and is the first line of host defense to prevent and control microorganisms such as P. carinii. Both innate and adaptive immunity influence alveolar host defense against P. carinii, and yet it is the AM that is ultimately responsible for recognition, phagocytosis, and destruction of the organism. With HIV infection or immunosuppression from any cause, defects in the alveolar host defense occur; to a large degree, these deficiencies permit development of P. carinii infection (Figure 1). Surprisingly, the mechanisms underlying critical disturbances in AM function during immunosuppression are not well understood.
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We are all likely exposed to P. carinii sometime during our lifetime (1). P. carinii pneumonia occurs when P. carinii escape detection and clearance by the immune system. P. carinii attach to alveolar epithelial cells as an obligate extracellular parasite and enter the stage of the life cycle required for replication (2, 3). Attachment and phagocytosis of P. carinii by AMs is a critical first step in the initiation of the immune response and the eventual clearance of the organism. Avoidance of AMs by P. carinii is likely a key to their survival in the alveolar spaces. If AMs are depleted in the lungs, there is impaired clearance of P. carinii and progression of the pneumonia (4).
AMs require a host of activating cytokines to maximize
their ability to detect and clear pathogens such as P. carinii. These include but are not limited to interferon 
(IFN-), tumor necrosis factor 
(TNF-), and granulocyte macrophage colony-stimulating factor (GM-CSF). Viral infections such as HIV can obviously deplete important
immune effector cells such as T lymphocytes and therefore diminish a major source of cytokines that might activate
AMs in host defense. When properly activated by IFN-,
AMs can effectively destroy P. carinii organisms (5).
IFN- and TNF- are both important cytokines in the control of P. carinii infection (8). GM-CSF is also important in stimulating clearance of P. carinii in vivo, likely by
a TNF-dependent mechanism (11, 12).
Following ingestion AMs can destroy microorganisms
such as P. carinii. Both reactive oxygen intermediates and
reactive nitrogen intermediates are important antimicrobial mechanisms that mediate killing of P. carinii (9, 13,
14). These AM-mediated killing mechanisms of P. carinii
may be mediated by TNF- (9).
T lymphocytes are critically important in host defense to P. carinii. It is known that CD4+ lymphocytes are required for adequate host defense from P. carinii (15, 16). In fact, CD4 lymphocyte depletion is now a standard method for establishing P. carinii pneumonia in mice (17, 18). Clinically, it is well known that susceptibility to P. carinii infection in HIV-infected subjects is directly related to the degree of CD4 lymphocyte depletion (18, 19). There are also several reports that indicate that B lymphocytes and immunoglobulins serve as an important host defense to P. carinii (20, 21).
Immunosuppression greatly facilitates P. carinii infection
because it can produce impairment in both peripheral blood
(T and B lymphocytes) and lung (AM) immune cells. The
most common causes of immunosuppression associated with
opportunistic pulmonary infections such as P. carinii include
HIV disease, cytotoxic chemotherapy, and corticosteroids
(22). Although the immunosuppressive effects of these
agents vary, they share an ability to directly impair function
or reduce absolute numbers of T and B lymphocytes (26, 39). AMs are also adversely affected in an indirect way because they require lymphocyte-derived products, such as
IFN-, to be maximally effective in host defense (6, 35).
However, the same agents that induce immunosuppression
also directly impair AM function (27, 29, 31, 33). Thus, immunosuppression has the potential to significantly impair
AM function both directly and indirectly.
In the current issue of the Journal, Koziel and coworkers demonstrate that AMs from HIV-infected subjects have an inadequate oxidative response to P. carinii (38). The inability of AMs to generate an oxidative burst was inversely proportional to the CD4 lymphocyte count. Their study does not directly determine whether the impaired AM oxidative burst is due to a direct effect of HIV infection or indirectly due to interference with specific signaling or cytokine pathways. It is clear from multiple studies that alveolar host defense is markedly impaired in HIV subjects, and for yet poorly understood reasons, P. carinii appears to be uniquely well positioned to become an opportunistic pathogen in HIV-infected subjects. An improved understanding of the mechanisms underlying this observation by Koziel and coworkers may provide clues to this unique predisposition to P. carinii infection in HIV-infected subjects.
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Footnotes |
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Address correspondence to: William J. Martin II, M.D., Indiana University School of Medicine, Department of Medicine, Division of Pulmonary, Allergy, Critical Care, and Occupational Medicine, 1001 West 10th St. OPW 425, Indianapolis, IN 46202-2879. E-mail: wjmartin{at}iupui.edu
(Received in original form August 12, 2000).
Abbreviations
AM(s), alveolar macrophage(s);
IFN-, interferon ;
HIV, human immunodeficiency virus;
TNF-, tumor necrosis factor .
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