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Papers by Terry Wright

American Journal of Physiology-lung Cellular and Molecular Physiology, Dec 1, 2006

Cold Spring Harbor Perspectives in Medicine, Nov 3, 2014

Infection and Immunity, Feb 1, 2001

PLOS Pathogens, Nov 29, 2012

Infection and Immunity, Oct 1, 2004

Journal of Immunology, Jul 15, 2008

Infection and Immunity, Jan 22, 2020

The pulmonary immune response protects healthy individuals against Pneumocystis pneumonia (PcP). ... more The pulmonary immune response protects healthy individuals against Pneumocystis pneumonia (PcP). However, the immune response also drives immunopathogenesis in patients who develop severe PcP, and it is generally accepted that optimal treatment requires combination strategies that promote fungal killing and also provide effective immunomodulation. The anti-inflammatory drug sulfasalazine programs macrophages for enhanced Pneumocystis phagocytosis and also suppresses PcP-related immunopathogenesis. Anti-Pneumocystis antibody opsonizes Pneumocystis organisms for greater phagocytosis and may also mask antigens that drive immunopathogenesis. Thus, we hypothesized that combining antibody and sulfasalazine would have the dual benefit of enhancing fungal clearance while dampening immunopathogenesis and allow the rescue of severe PcP. To model a clinically relevant treatment scenario in mice, therapeutic interventions were withheld until clear symptoms of pneumonia were evident. When administered individually, both passive antibody and sulfasalazine improved pulmonary function and enhanced Pneumocystis clearance to similar degrees. However, combination treatment with antibody and sulfasalazine produced a more rapid improvement, with recovery of body weight, a dramatic improvement in pulmonary function, reduced lung inflammation, and the rapid clearance of the Pneumocystis organisms. Accelerated fungal clearance in the combination treatment group was associated with a significant increase in macrophage phagocytosis of Pneumocystis. Both passive antibody and sulfasalazine resulted in the suppression of Th1 cytokines and a marked increase in lung macrophages displaying an alternatively activated phenotype, which were enhanced by combination treatment. Our data support the concept that passive antibody and sulfasalazine could be an effective and specific adjunctive therapy for PcP, with the potential to accelerate fungal clearance while attenuating PcP-associated immunopathogenesis.

Infection and Immunity, May 1, 2005

Pneumocystis carinii pneumonia (PcP) is a clinically important infection of immunocompromised pat... more Pneumocystis carinii pneumonia (PcP) is a clinically important infection of immunocompromised patients. Although the interaction of Pneumocystis with the alveolar epithelium has been well documented, very little information regarding the epithelial response to Pneumocystis is currently available. In order to study Pneumocystis-epithelium interactions, a murine cell line derived specifically from an alveolar epithelial cell (AEC) was utilized. The coculture of murine AECs with mouse Pneumocystis induced a dose-and time-dependent release of the CXC chemokine MIP-2. Importantly, the specific removal of Pneumocystis from the preparation, or the pretreatment of AECs with sulfasalazine, a potent and specific inhibitor of NF-B, nearly completely abrogated the chemokine response to Pneumocystis. Since the murine MIP-2 promoter contains consensus B binding sequences, the ability of Pneumocystis to stimulate NF-B signaling in AECs was examined. Pneumocystis stimulation of an AEC line stably transfected with a B-dependent reporter construct triggered the NF-B signaling pathway and reporter production. These data were confirmed in gel shift assays, providing direct evidence that Pneumocystis induced the nuclear translocation of the p50/p65 heterodimeric form of NF-B. Maximal NF-B activation was dependent upon direct contact with viable Pneumocystis organisms. These data demonstrate that Pneumocystis activates NF-B signaling in AECs and establish a reporter cell line for studying NF-B activation in AECs. Given the global regulatory functions of the NF-B family, these findings suggest that Pneumocystis directly alters AEC gene expression in a manner that promotes pulmonary immune and inflammatory responses.

Interdisciplinary Perspectives on Infectious Diseases, 2011

Pneumocystis is an opportunistic fungal respiratory pathogen that causes life-threatening pneumon... more Pneumocystis is an opportunistic fungal respiratory pathogen that causes life-threatening pneumonia (Pcp) in patients suffering from defects in cell-mediated immunity, including those with acquired immunodeficiency syndrome (AIDS) and immunosuppression secondary to chemotherapy or organ transplantation. Despite major advances in health care, the mortality associated with Pcp has changed little over the past 25 years. Pcp remains a leading cause of death among HIV infected patients, with mortality rates of 50% or higher for patients developing severe Pcp. In addition, as more potent immunosuppressive therapies are developed for chronic inflammatory diseases, more cases of Pcp are occurring in non-HIV patients and in previously unreported clinical settings. These features highlight the importance of developing a better understanding of the pathogenesis of this disease, and the need to search for new therapeutic strategies to improve the outcome of Pcp patients. Immune-mediated inflammatory responses play an important role in the pathogenesis of Pcp, and may be even more significant in determining the outcome of Pcp than direct damage due to the organism itself. In this review we will summarize the immunopathogenic mechanisms that contribute to Pcp-associated lung injury, and discuss the potential to target these pathways for adjunctive immune modulation therapy for Pcp.

Infection and Immunity, 2006

Pneumocystis carinii is an opportunistic fungal pathogen that causes P. carinii pneumonia (PCP) i... more Pneumocystis carinii is an opportunistic fungal pathogen that causes P. carinii pneumonia (PCP) in the immunocompromised host. We investigated the role of antibody Fc-mediated function in passive prophylaxis against the development of PCP in SCID mice. By comparison of anti-mouse P. carinii immunoglobulin G1 monoclonal antibody (MAb) 4F11(G1) and its F(ab)2 derivative in an intranasal immunoprophylaxis model, we determined that Fc-mediated function is required for maximum effect of this antibody. Comparison of efficacy of antibody prophylaxis in SCID mice depleted of complement to that in nondepleted mice demonstrated that complement fixation by MAb 4F11(G1) is also necessary for optimal effect of passively administered antibody, although residual protection was observed in complement-depleted SCID mice. The necessity of complement for optimal PCP prophylaxis by MAb 4F11(G1) suggests that complement may play a role in antibody-mediated protection against development of PCP. Pneumocystis carinii is an opportunistic fungal pathogen that causes pneumonia in the immunocompromised host. The primary requirement for protection against P. carinii pneumonia (PCP) is normal CD4 ϩ T-cell function (7, 17, 27), though mice and humans with B-cell deficiencies are also susceptible to PCP (16, 25), suggesting a role for antibody in protection. Although drug treatments for P. carinii pneumonia exist, poor compliance to drug treatment schedules, recurrent infections, and adverse side effects to the drugs are problems (9, 19). Therefore, investigation of host-parasite interactions which could lead to new treatment methods is worthwhile. A growing body of evidence suggests that anti-Pneumocystis antibody therapy may be an effective means of preventing and treating PCP. Hyperimmune sera from mice immunized with P. carinii organisms resolved existing P. carinii infections in SCID mice and decreased the hyperinflammatory reaction inimmune-reconstituted mice (23, 24). An early study using an anti-mouse P. carinii antibody demonstrated partial protection against development of PCP (1). Our previous studies demonstrated that SCID mice are also protected from the development of PCP by passive prophylaxis using the anti-P. carinii immunoglobulin M (IgM) monoclonal antibody (MAb) 4F11 or its IgG1 switch variant, MAb 4F11(G1) (2). MAb 4F11(G1) recognizes multiple, similar epitopes on the surface of P. carinii isolated from mice within at least two different antigens, kexin and cDNA clone A12 (13, 29). MAb 4F11(G1) is also capable of recognizing P. carinii derived from humans, rhesus macaques, rats, and ferrets (2, 29). In this investigation, we set out to determine the mechanism of protection against development of PCP by MAb 4F11(G1). Specifically, we wanted to determine whether protection by MAb 4F11(G1) was mediated through antibody Fc region

Infection and Immunity, Apr 1, 2006

Mice immunized with recombinant mouse Pneumocystis carinii antigen A12-thiredoxin fusion protein ... more Mice immunized with recombinant mouse Pneumocystis carinii antigen A12-thiredoxin fusion protein developed an antibody response that recognized P. carinii antigens, as determined by Western blotting and immunofluorescence analysis. Compared to mice immunized with thioredoxin alone, mice immunized with A12thioredoxin had significantly reduced lung P. carinii burdens after CD4 ؉ T-cell depletion and challenge with P. carinii.

Journal of Immunology, 2014

The immune response protects against Pneumocystis infection, but is also a key component of PcP-r... more The immune response protects against Pneumocystis infection, but is also a key component of PcP-related immunopathogenesis. Signaling through MyD88 is critical for activation of immune pathways downstream of TLRs and IL-1 receptor. To determine whether MyD88 regulates normal host defense against Pneumocystis, non-immunosuppressed wild-type (WT) and MyD88 deficient mice were infected. MyD88 −/− mice had higher early Pneumocystis burdens than WT mice, but mounted an effective adaptive immune response and cleared Pneumocystis similar to WT. However, MyD88 −/− mice displayed a more intense and prolonged pulmonary immune response than WT mice. To determine the role of MyD88 in the development of PcP-related immunopathogenesis, WT and MyD88 −/− mice were rendered susceptible to PcP by depletion of CD4 + T cells. At 4 weeks post-infection, CD4-depleted WT and MyD88 −/− mice harbored similar organism burdens, but MyD88 −/− mice were protected from the PcP-related respiratory impairment observed in WT mice. Improved pulmonary physiology in MyD88 −/− mice correlated with lower lung CCL2 levels, and reduced cell recruitment. However, by 5 weeks post-infection the overall health of MyD88 −/− mice began to deteriorate rapidly relative to WT, with accelerated weight loss, impaired lung function, and exacerbated alveolar inflammation. This physiological decline of MyD88 −/− mice was associated with increased TNF-α and IFN-γ in the lung, and by the inability to control Pneumocystis burden. Thus, MyD88 is not required for resistance to Pneumocystis infection, but limits the adaptive immune response in immunocompetent mice. In the setting of active PcP, MyD88 signaling contributes to both immunopathogenesis and control of fungal burden.

Journal of Immunology, Feb 15, 2004

CD8 ؉ T cells contribute to the pathophysiology of Pneumocystis pneumonia (PcP) in a murine model... more CD8 ؉ T cells contribute to the pathophysiology of Pneumocystis pneumonia (PcP) in a murine model of AIDS-related disease. The present studies were undertaken to more precisely define the mechanisms by which these immune cells mediate the inflammatory response that leads to lung injury. Experimental mice were depleted of either CD4 ؉ T cells or both CD4 ؉ and CD8 ؉ T cells and then infected with Pneumocystis. The CD4 ؉-depleted mice had significantly greater pulmonary TNF-␣ levels than mice depleted of both CD4 ؉ and CD8 ؉ T cells. Elevated TNF-␣ levels were associated with increased lung concentrations of the chemokines RANTES, monocyte chemoattractant protein 1, macrophage-inflammatory protein 2, and cytokine-induced neutrophil chemoattractant. To determine whether TNFR signaling was involved in the CD8 ؉ T cell-dependent chemokine response, TNFRI-and II-deficient mice were CD4 ؉ depleted and infected with Pneumocystis. TNFR-deficient mice had significantly reduced pulmonary RANTES, monocyte chemoattractant protein 1, macrophage-inflammatory protein 2, and cytokine-induced neutrophil chemoattractant responses, reduced inflammatory cell recruitment to the alveoli, and reduced histological evidence of PcP-related alveolitis as compared with infected wild-type mice. Diminished pulmonary inflammation correlated with improved surfactant activity and improved pulmonary function in the TNFR-deficient mice. These data indicate that TNFR signaling is required for maximal CD8 ؉ T cell-dependent pulmonary inflammation and lung injury during PcP and also demonstrate that CD8 ؉ T cells can use TNFR signaling pathways to respond to an extracellular fungal pathogen.

American Journal of Physiology-lung Cellular and Molecular Physiology, Jun 1, 2006

and Jack Finkelstein. Pneumocystis carinii infection sensitizes lung to radiation-induced injury ... more and Jack Finkelstein. Pneumocystis carinii infection sensitizes lung to radiation-induced injury after syngeneic marrow transplantation: role of CD4 ϩ T cells.

Journal of Immunology, Sep 27, 2013

Pneumocystis is an atypical fungal pathogen which causes severe, often fatal pneumonia (PcP) in i... more Pneumocystis is an atypical fungal pathogen which causes severe, often fatal pneumonia (PcP) in immunocompromised patients. Healthy humans and animals also encounter this pathogen, but generate a protective CD4 + T cell dependent immune response that clears the pathogen with little evidence of disease. Pneumocystis organisms attach tightly to respiratory epithelial cells, and in vitro studies have demonstrated that this interaction triggers NF-B-dependent epithelial cell responses. However, the contribution of respiratory epithelial cells to the normal host response to Pneumocystis remains unknown. Inhibitor of B Kinase 2 (IKK2) is the upstream kinase that is critical for inducible NF-B activation. To determine whether IKK2-dependent lung epithelial cell responses contribute to the anti-Pneumocystis immune response in vivo, transgenic mice with lung epithelial cell-specific deletion of IKK2 (IKK2 LEC) were generated. Compared to wild type mice, IKK2 LEC mice exhibited a delayed onset of Th17 and B cell responses in the lung, and delayed fungal clearance. Importantly, delayed Pneumocystis clearance in IKK2 LEC mice was associated with an exacerbated immune response, impaired pulmonary function, and altered lung histology. These data demonstrate that IKK2-dependent lung epithelial cell responses are important regulators of pulmonary adaptive immune responses, and are required for optimal host defense against Pneumocystis infection. LECs likely set the threshold for initiation of the pulmonary immune response, and serve to prevent exacerbated lung inflammation by promoting the rapid control of respiratory fungal infection. genetically distinct, and attempts at cross-species transmission have not been successful [1-3]. Furthermore, the requirements for Pneumocystis growth in vitro have not been determined, making the study of life cycle and biology a significant challenge.

American Journal of Physiology-lung Cellular and Molecular Physiology, Jun 1, 2005

This study examines the direct inhibitory effects of Pneumocystis carinii (Pc) organisms and chem... more This study examines the direct inhibitory effects of Pneumocystis carinii (Pc) organisms and chemical components on the surface activity and composition of whole calf lung surfactant (WLS) and calf lung surfactant extract (CLSE) in vitro. Incubation of WLS suspensions with intact Pc organisms (10 7 per milligram of surfactant phospholipid) did not significantly alter total phospholipid levels or surfactant protein A content. Incubation with intact Pc organisms also did not impair dynamic surface tension lowering in suspensions of WLS or centrifuged large surfactant aggregates on a bubble surfactometer (37°C, 20 cycles/min, 0.5 and 2.5 mg phospholipid/ml). However, exposure of WLS or CLSE to disrupted (sonicated) Pc organisms led to severe detriments in activity, with minimum surface tensions of 17-19 mN/m vs. Ͻ1 mN/m for surfactants alone. Extracted hydrophobic chemical components from Pc (98.8% lipids, 0.1 mM) reduced the surface activity of WLS and CLSE similarly to sonicated Pc organisms, whereas extracted hydrophilic chemical components from Pc (primarily proteins) had only minor effects on surface tension lowering. These results indicate that in addition to surfactant dysfunction induced by inflammatory lung injury and edema-derived inhibitors in Pc pneumonia, disrupted Pc organisms in the alveolar lumen also have the potential to directly inhibit endogenous and exogenous lung surfactants in affected patients. lung surfactant; surfactant dysfunction; lung injury PNEUMOCYSTIS CARINII (Pc) is an opportunistic microorganism that is widely disseminated in the general population (10, 24, 29, 47). Although benign under normal circumstances, Pc can cause life-threatening pneumonia in immunocompromised hosts. Pc pneumonia (PcP) is a major presenting complaint in patients with acquired immune deficiency syndrome (10, 24, 25, 29, 47). PcP is also common in immunosuppressed patients undergoing organ transplant or bone marrow transplant or receiving therapy for hematological or other malignancies (7, 10, 41). Mortality rates for PcP in immune-compromised patients in intensive care units are substantial, ranging from 8 to 60% depending on the patient groups involved (7, 10, 24, 25, 29, 41, 47). Despite the prevalence and medical importance of PcP, many of the pathophysiological mechanisms by which Pc produces clinical signs and symptoms remain relatively poorly understood.

Infection and Immunity, 1998

Pneumocystis carinii is an important pulmonary pathogen responsible for morbidity and mortality i... more Pneumocystis carinii is an important pulmonary pathogen responsible for morbidity and mortality in patients with AIDS. The acute-phase response (APR), the primary mechanism used by the body to restore homeostasis following infection, is characterized by increased levels of circulating fibrinogen (FBG). Although the liver is the primary site of increased FBG synthesis during the APR, we unexpectedly discovered that FBG is synthesized and secreted by lung alveolar epithelial cells in vitro during an inflammatory stimulus. Therefore, we sought to determine whether lung epithelial cells produce FBG in vivo using animal models of P. carinii pneumonia (PCP). Inflammation was noted by an influx of macrophages to P. carinii-infected alveoli. Northern hybridization revealed that ␥-FBG mRNA increased two-to fivefold in P. carinii-infected lung tissue, while RNA in situ hybridization demonstrated increased levels of ␥-FBG mRNA in the lung epithelium. Immunoelectron microscopy detected lung epithelial cell-specific production of FBG, suggesting induction of a localized inflammatory response resembling the APR. A systemic APR was confirmed by a two-to fivefold upregulation of the levels of hepatic ␥-FBG mRNA in animals with PCP, resulting in a corresponding increase in levels of FBG in plasma. Furthermore, immunoelectron microscopy revealed the presence of FBG at the junction of cell membranes of trophic forms of P. carinii organisms aggregated along the alveolar epithelium. These results implicate FBG in the pathogenesis of PCP in a manner similar to that of the adhesive glycoproteins fibronectin and vitronectin, which are known to participate in intra-alveolar aggregation of organisms and adherence of P. carinii to the lung epithelium.

DNA Research, 1995

Two ferret P. carinii gpA cDNA clones were identified that reacted identically with a panel of an... more Two ferret P. carinii gpA cDNA clones were identified that reacted identically with a panel of anti-gpA monoclonal antibodies, although their nucleotide sequences were 22% divergent. Each clone hybridized to a single mRNA species of 3,600 nucleotides only in P. carinii-mfected lung mRNA, but RT-PCR analysis demonstrated that these cDNA clones were derived from two distinct gpA mRNA transcripts. Further PCR analysis demonstrated that the ferret P. carinii genome contains at least two gpA genes lying in tandem on a single chromosome separated by a 329-bp intergenic region. Based on the terminal gene sequences of this tandem repeat and the cDNA clones, a composite full-length ferret P. carinii gpA coding sequence was constructed. The intergenic region immediately downstream of the stop codon of the first gpA gene contains three putative polyadenylation signals, and constitutes the 3' untranslated region (UTR) of the gpA mRNA. Primer extension of the gpA mRNA resulted in products extending 74 and 244 nucleotides into the 5' UTR. However, the intergenic region lying greater than 25 nucleotides upstream of the first methionine of the second gpA gene was found to be absent from the 5' UTR.

American Journal of Respiratory Cell and Molecular Biology, 1997

Severe combined immunodeficient (scid) mice lack functional CD4 ϩ lymphocytes, and therefore deve... more Severe combined immunodeficient (scid) mice lack functional CD4 ϩ lymphocytes, and therefore develop life-threatening Pneumocystis carinii infection. However, when scid mice are immunologically reconstituted with spleen cells, including CD4 ϩ cells, a protective inflammatory response is mounted against the organism. To determine whether these lymphocytes induce elevated cytokine mRNA levels in response to P. carinii infection, steady-state levels of cytokine mRNAs were measured in the lungs of both reconstituted and unaltered scid mice. Despite significant numbers of organisms and the presence of functional alveolar macrophages in the lungs of 8-and 10-wk-old scid mice, there was neither evidence of pulmonary inflammation, nor increased proinflammatory cytokine expression. However, when 8-wk-old scid mice were immunologically reconstituted, signs of intense, focal pulmonary inflammation were observed, and levels of interleukin (IL)-1 ␣ , IL-1 ␤ , IL-3, IL-6, interferon-␥ (IFN-␥), tumor necrosis factor (TNF)-␣ , and TNF-␤ mRNAs were all significantly elevated. Cytokine expression was increased at day 10 post-reconstitution (PR), maximal at day 12 PR, and returned to baseline by day 22 PR. In situ hybridization demonstrated that at day 12 PR, increased IL-1 ␤ and TNF-␣ expression was localized to sites of intense inflammation and focal P. carinii colonization. Many of the cells expressing high levels of IL-1 ␤ and TNF-␣ in these regions were in direct contact with organisms, or contained degraded organisms within their cytoplasm. Thus, even though functional macrophages are present in scid mice, CD4 ϩ T cells are required for proinflammatory cytokine expression, which is associated with the generation of a protective inflammatory response at sites of P. carinii infection. Wright, T. W., C. J. Johnston, A. G. Harmsen, and J. N. Finkelstein. 1997. Analysis of cytokine mRNA profiles in the lungs of Pneumocystis carinii-infected mice. Am. J. Respir. Cell Mol. Biol. 17:491-500.