Exposure of Immunocompetent Adult Mice to
 Pneumocystis carinii
 f. sp.
 muris
 by Cohousing: Growth of
 P
 .
 carinii
 f. sp.
 muris
 and Host Immune Response

An, Chun Li; Gigliotti, Francis; Harmsen, Allen G.

doi:10.1128/iai.71.4.2065-2070.2003

Cited by 60 publications

(51 citation statements)

References 27 publications

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“…We suggest that the overall inflammatory response and outcome of infection with P. carinii is dependent on the balance between CD4 ϩ and CD8 ϩ T cells. With a balanced or physiological response, as would be seen in the normal host, infection is easily cleared with minimal inflammation and little apparent "disease" (2,14). With a CD4 ϩ T cell dominant response in the absence of adequate CD8 ϩ T cell suppression, e.g., as might be seen in IRD, infection is rapidly cleared but at the expense of excessive inflammation and bystander injury to the lung (as shown in this study).…”

Section: Discussionmentioning

confidence: 70%

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Contribution of T cell subsets to the pathophysiology ofPneumocystis-related immunorestitution disease

Bhagwat

Gigliotti²,

Xu³

et al. 2006

American Journal of Physiology-Lung Cellular and Molecular Phys

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.-Immune-mediated lung injury is an important component of Pneumocystis pneumonia (PcP)-related immunorestitution disease (IRD). However, the individual contribution of CD4 ϩ and CD8 ϩ T cells to the pathophysiology of IRD remains undetermined. Therefore, IRD was modeled in severe combined immunodeficient mice, and specific T cell depletion was used to determine how T cell subsets interact to affect the nature and severity of disease. CD4 ϩ cells were more abundant than CD8 ϩ cells during the acute stage of IRD that coincided with impaired pulmonary physiology and organism clearance. Conversely, CD8 ϩ cells were more abundant during the resolution phase following P. carinii clearance. Depletion of CD4 ϩ T cells protected mice from the acute pathophysiology of IRD. However, these mice could not clear the infection and developed severe PcP at later time points when a pathological CD8 ϩ T cell response was observed. In contrast, mice depleted of CD8 ϩ T cells efficiently cleared the infection but developed more severe disease, an increased frequency of IFN-␥-producing CD4 ϩ cells, and a prolonged CD4 ϩ T cell response than mice with both CD4 ϩ and CD8 ϩ cells. These data suggest that CD4 ϩ T cells mediate the acute respiratory disease associated with IRD. In contrast, CD8 ϩ T cells contributed to neither lung injury nor organism clearance when CD4 ϩ cells were present, but instead served to modulate CD4 function. In the absence of CD4 ϩ cells, CD8 ϩ T cells produced a nonprotective, pathological immune response. These data suggest that the interplay of CD4 ϩ and CD8 ϩ T cells affects the ultimate outcome of PcP-related IRD.inflammation; pulmonary physiology; acquired immune deficiency syndrome PNEUMOCYSTIS carinii IS an opportunistic fungus that causes pneumonia in immune-compromised patients (37), including patients with acquired immune deficiency syndrome (AIDS) (29), patients undergoing chemotherapy, and patients receiving treatment with immunosuppressive drugs during organ transplantation (34). Although exposure to P. carinii is nearly universal, as demonstrated by the appearance of anti-P. carinii antibody in 85% of children by the age of 20 mo (35), a period of immunosuppression is essential for the development of clinical disease (15,34). Several studies have demonstrated a positive correlation between the degree of inflammation and the severity of disease (4,23,36), suggesting that the pathogenesis of Pneumocystis pneumonia (PcP) is primarily inflammatory in nature, in that infection with P. carinii is necessary to cause pneumonia, but certain aspects of the immune response against P. carinii are responsible for the associated pathophysiology (30, 39). For example, AIDS patients who demonstrate a rapid recovery of CD4 ϩ T lymphocytes after institution of combined antiretroviral therapy may develop pulmonary decompensation in response to preexisting pulmonary infections, including P. carinii (26). This clinical syndrome has been termed "immunorestitution disease" (IRD) (9). At least one study that examined t...

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Section: Discussionmentioning

confidence: 70%

“…Based on this study and our previously published experiments (2,14,39,40), we propose the following conceptual framework to think about how T cells affect the outcome of PcP. We suggest that the overall inflammatory response and outcome of infection with P. carinii is dependent on the balance between CD4 ϩ and CD8 ϩ T cells.…”

Section: Discussionmentioning

confidence: 99%

Contribution of T cell subsets to the pathophysiology ofPneumocystis-related immunorestitution disease

Bhagwat

Gigliotti²,

Xu³

et al. 2006

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Immunosuppressed rodents housed in a room with other rodents with acute PCP will develop PCP (246,322). In a series of experiments, investigators found that immunocompetent mice exposed to mice with PCP could transmit Pneumocystis to other immunocompetent mice (4,99). When these immunocompetent, PCP-exposed mice were cohoused with immunosuppressed mice, the immunosuppressed animals developed PCP, thus directly implicating intraspecies transmission as an important mechanism.…”

Section: De Novo Infectionmentioning

confidence: 99%

“…Pneumocystis-colonized individuals might also serve as a reservoir for disease transmission. As discussed above, colonized animals can transmit colonization to other animals and can also transmit disease to immunocompromised hosts (4,99). Evidence of person-to-person transmission of PCP as well as detection of colonization in health care workers suggests that the organism might pass through a colonized host before causing disease (56,57,94,176,186,215,288).…”

Section: Role In Diseasementioning

confidence: 99%

Colonization by Pneumocystis jirovecii and Its Role in Disease

2012

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SUMMARY Although the incidence of Pneumocystis pneumonia (PCP) has decreased since the introduction of combination antiretroviral therapy, it remains an important cause of disease in both HIV-infected and non-HIV-infected immunosuppressed populations. The epidemiology of PCP has shifted over the course of the HIV epidemic both from changes in HIV and PCP treatment and prevention and from changes in critical care medicine. Although less common in non-HIV-infected immunosuppressed patients, PCP is now more frequently seen due to the increasing numbers of organ transplants and development of novel immunotherapies. New diagnostic and treatment modalities are under investigation. The immune response is critical in preventing this disease but also results in lung damage, and future work may offer potential areas for vaccine development or immunomodulatory therapy. Colonization with Pneumocystis is an area of increasing clinical and research interest and may be important in development of lung diseases such as chronic obstructive pulmonary disease. In this review, we discuss current clinical and research topics in the study of Pneumocystis and highlight areas for future research.

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“…Anti-Pneumocystis antibodies in serum samples from experimental mice were measured as previously described (28,29). Briefly, flat-bottom microtiter plates (ICM Biomedical, Aurora, OH) were coated overnight with mouse Pneumocystis antigen (in 0.05 M carbonate buffer, pH 9.6) at room temperature.…”

Section: Micementioning

confidence: 99%

Neither Classical nor Alternative Macrophage Activation Is Required for Pneumocystis Clearance during Immune Reconstitution Inflammatory Syndrome

et al. 2015

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c Pneumocystis is a respiratory fungal pathogen that causes pneumonia (Pneumocystis pneumonia [PcP]) in immunocompromised patients. Alveolar macrophages are critical effectors for CD4؉ T cell-dependent clearance of Pneumocystis, and previous studies found that alternative macrophage activation accelerates fungal clearance during PcP-related immune reconstitution inflammatory syndrome (IRIS). However, the requirement for either classically or alternatively activated macrophages for Pneumocystis clearance has not been determined. Therefore, RAG2؊/؊ mice lacking either the interferon gamma (IFN-␥) receptor (IFN-␥R) or interleukin 4 receptor alpha (IL-4R␣) were infected with Pneumocystis. These mice were then immune reconstituted with wild-type lymphocytes to preserve the normal T helper response while preventing downstream effects of Th1 or Th2 effector cytokines on macrophage polarization. As expected, RAG2 cell responses in RAG/IFN-␥R؊/؊ mice were associated with elevated lung IFN-␥ levels, and neutralization of IFN-␥ restored the CD8 response. These data demonstrate that restricting the ability of macrophages to polarize in response to Th1 or Th2 cytokines does not impair Pneumocystis clearance. However, a cell type-specific IFN-␥/IFN-␥R-dependent mechanism regulates CD8 ؉ T suppressor cell recruitment, limits immunopathogenesis, preserves lung function, and enhances the resolution of PcPrelated IRIS. Pneumocystis is an opportunistic fungal pathogen, which is widespread throughout the human population. Vargas et al. reported that nearly 85% of children have been exposed to Pneumocystis by 20 months of age (1). The infection appears mild and self-limited in a normal host, but Pneumocystis causes life-threatening pneumonia in patients with defects in cell-mediated immunity. Pneumocystis pneumonia (PcP) remains prevalent in those with AIDS (2) and is a leading cause of death in HIV-infected patients, with a mortality rate of up to 50% in those with severe disease (3). Pneumocystis also infects patients receiving long-term immunomodulatory therapy for rheumatoid arthritis and other inflammatory diseases (4) as well as cancer patients undergoing chemotherapy (5). Furthermore, Pneumocystis infection or colonization has been associated with chronic obstructive pulmonary disease in both HIV and non-HIV patients (6).Despite the availability of antibiotics that effectively eradicate Pneumocystis, rapid clinical improvement is not always observed in patients with PcP. The host's immune response against this pathogen often contributes to severe PcP-related lung injury (6, 7). Clinical studies suggest that the intensity of pulmonary inflammation, rather than organism lung burden, correlates with the severity of PcP (8-10). Furthermore, rapid and unbalanced restoration of cell-mediated immunity following antiretroviral treatment of Pneumocystis-infected HIV patients sometimes results in exaggerated lung inflammation and leads to the clinical manifestation of immune reconstitution inflammatory syndrome (IRIS) (11). IRIS is an...

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Exposure of Immunocompetent Adult Mice to Pneumocystis carinii f. sp. muris by Cohousing: Growth of P . carinii f. sp. muris and Host Immune Response

Cited by 60 publications

References 27 publications

Contribution of T cell subsets to the pathophysiology ofPneumocystis-related immunorestitution disease

Contribution of T cell subsets to the pathophysiology ofPneumocystis-related immunorestitution disease

Colonization by Pneumocystis jirovecii and Its Role in Disease

Neither Classical nor Alternative Macrophage Activation Is Required for Pneumocystis Clearance during Immune Reconstitution Inflammatory Syndrome

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