Absence of the macrophage mannose receptor in mice does not increase susceptibility to Pneumocystis carinii infection in vivo.

Pulmonary host defense typically involves cooperation among many cell types, including resident epithelium and macrophages as well as circulating inflammatory cells. However, the importance of each type of cell may differ, depending on the nature of the pathogen presented. Infection with the opportunistic fungus Pneumocystis carinii, which causes often-fatal pneumonia in immunocompromised patients, is an example of a disease process in which many cell types have important but distinct roles. The appearance of antibodies against P. carinii by age 2 in most children, coupled with the low occurrence of the disease in healthy people, led early investigators to conclude that humoral immunity and B cells were of primary importance in host defense against P. carinii (reviewed in reference 68). However, the high incidence of P. carinii infections in AIDS patients (42, 43) and later experimental mouse models highlights the crucial importance of CD4+ lymphocytes in the control of P. carinii infections (5, 20). In spite of their importance, CD4+ lymphocytes are probably not involved with the major effector mechanisms against P. carinii (21, 52); instead, this role probably falls to CD8+ lymphocytes, antibodies, and macrophages. Although the importance of CD8+ cells in defense against P. carinii (3, 27) as well as their role in host tissue damage (74) is evident, the mechanisms by which these cells cause these responses are not clear. And although there have been many investigations into the interactions of alveolar macrophages with P. carinii, many of the mechanisms that facilitate elimination of P. carinii by these cells are also still unclear. Alveolar macrophages will bind and phagocytose P. carinii in vitro (30, 67), and these events are followed by degradation of P. carinii (35). And in an in vivo rat study, depletion of alveolar macrophages resulted in decreased clearance of P. carinii (35). The interaction of P. carinii with alveolar macrophages also results in the stimulation of other functions, including the production of reactive oxygen species (22), reactive nitrogen species (57), and certain cytokines (23, 69). In spite of this strong response to P. carinii, alveolar macrophages are apparently not sufficient to clear P. carinii infections in situations where other immune cell function is compromised, such as the absence of lymphocytes in the SCID mouse (10), the selective depletion of CD4+ lymphocytes by antibody injection in mice (4), and in human immunodeficiency virus (HIV)-infected humans that have diminished numbers of CD4+ lymphocytes (28) (although HIV may directly affect macrophages as well). Because of this, attention has been focused on which specific alveolar macrophage functions are necessary for the elimination of P. carinii and how other conditions, such as HIV infections and/or the depletion of CD4+ lymphocytes, may affect those functions. One macrophage function that has come under scrutiny is the surface receptors by which P. carinii binds to macrophages. Several proteins may be involved in this interaction, including a putative β-glucan receptor (12, 18), surfactant proteins D (45) and A (76), and vitronectin and fibronectin (64); however, most efforts have concentrated on the macrophage mannose receptor. This macrophage membrane glycoprotein binds P. carinii glycoprotein A (46) and is believed to be a primary receptor through which P. carinii is phagocytosed (13). Expression of the mannose receptor on the surface of alveolar macrophages is modulated by exogenous agents. Inflammatory stimuli, such as lipopolysaccharide (53), phorbol myristate acetate (11), gamma interferon (54), parasitic infection (1), and fungal infection (56), have all been shown to cause downregulation of the macrophage mannose receptor. Conversely, treatment with the anti-inflammatory steroid dexamethasone results in significant upregulation of macrophage mannose receptors (54, 55). Additionally, there is evidence that TH2 polarization, and in particular interleukin 4, can cause upregulation of mannose receptors in elicited peritoneal macrophages, although it is not known if this occurs in alveolar macrophages (17, 61). The macrophage mannose receptor also appears to decrease in expression in HIV-infected humans, with and without concurrent P. carinii infection (28). What was especially interesting about that study was the correlation between the in vitro ability of alveolar macrophages taken from these individuals to phagocytose P. carinii and the relative expression of the mannose receptor on the surfaces of those cells. Furthermore, decreased expression of the mannose receptor on alveolar macrophages seemed to coincide with the relative decrease in the patient's level of CD4+ lymphocytes: that is, patients with the lowest CD4+ count tended to have the lowest level of expression of mannose receptor on their alveolar macrophages. This raises the interesting question of whether HIV infection causes increased susceptibility to P. carinii as a result of the decreased level of macrophage mannose receptor and any resultant impairment in macrophage function. Additionally, the question arises whether the decrease in macrophage function is a direct consequence of the decrease in CD4+ lymphocytes or is a consequence of HIV infection through another mechanism. These questions are especially relevant in light of a recent report on the mannose receptor and Candida infection (32). These authors show that although in vitro phagocytosis of Candida can be diminished by blocking mannose receptor function, mice genetically deficient in mannose receptors exhibit normal host defense against Candida. The implications of this are that redundant host defense mechanisms in vivo can compensate for the lack of an important fungal pathogen binding receptor. In light of this finding, we elected to examine the susceptibility to infection with P. carinii in mice that are genetically deficient for the mannose receptor, both with and without concurrent depletion of CD4+ lymphocytes.