Tumor Necrosis Factor-A and Host Resistance to ThePathogenic Fungus, Histoplasma Capsulatum

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Tumor Necrosis Factor-a and Host Resistance to the Pathogenic Fungus, Histoplasma capsulatum George S. Deepe Jr1 Tumor necrosis factor-alpha (TNF-a) is a multifunctional cytokine that is critically important in host defenses to a number of pathogenic microbes. Among those, this cytokine is necessary for control of infection with the pathogenic fungus, Histoplasma capsulatum. Antagonism of endogenous cytokine is associated with an enhanced susceptibility to histoplasmosis in both mice and humans.
  Tumor Necrosis Factor- a and Host Resistance to thePathogenic Fungus, Histoplasma capsulatum  George S. Deepe Jr 1 Tumor necrosis factor-alpha (TNF- a  ) is a multifunctional cytokine that is critically important in host defenses to anumber of pathogenic microbes. Among those, this cytokine is necessary for control of infection with thepathogenic fungus, Histoplasma capsulatum . Antagonism of endogenous cytokine is associated with anenhanced susceptibility to histoplasmosis in both mice and humans. The mechanisms by which TNF- a  modulates the protective immune response will be discussed.  Journal of Investigative Dermatology Symposium Proceedings  (2007) 12, 34–37. doi:10.1038/sj.jidsymp.5650026 INTRODUCTION Tumor necrosis factor alpha (TNF)- a is a multifunctionalcytokine generated by a wide range of cell populations. Oneof its major functions is related to host defenses. It is animportant stimulus in (1) the flux of inflammatory cells, (2) theformation of granulomas, (3) the generation of nitric oxide,and (4) the regulation of other cytokines and chemokines(Beutler and Cerami, 1989; Feldmann and Maini, 2001).TNF- a mediates its functions through engagement of tworeceptors, TNF receptor (TNFR)1 and 2. The receptors aredifferent in protein composition and binding to each receptorproduces different biochemical outcomes (Aggarwal, 2003).In several models of infectious diseases, the presence of endogenous TNF- a is crucial for effective host resistancemechanisms. Neutralization of this cytokine exacerbatesinfection with Mycobacterium tuberculosis  , Listeria mono- cytogenes  , Leishmania major  , and Toxoplasma gondii  (Flynn et al  ., 1995; Deckert-Schluter et al  ., 1998; White et al  ., 2000;Wilhelm et al  ., 2001; Botha and Ryffel, 2003; Schluter et al  .,2003; Serbina et al  ., 2003). Control of infections withpathogenic fungi also is dependent on the presence of TNF- a . Experimental candidiasis, aspergillosis, blastomycosis,andhistoplasmosisrequire thiscytokine for control of infectionor for vaccine-induced immunity (Smith et al  ., 1990; Wu-Hsieh et al  ., 1992; Steinshamn et al  ., 1996; Marino et al  .,1997; Allendoerfer and Deepe, 1998, 2000; Zhou et al  ., 1998;Mehrad et al  ., 1999; Finkel-Jimenez et al  ., 2002). Histoplasma capsulatum  is a pathogenic fungus that isfound in most areas of the world and is endemic to themidwestern and southeastern United States. Most infectionsare either clinically unapparent or manifest with a flu-likeillness that resolves without treatment. Microconidia orhyphal fragments are inhaled from the soil, deposit withinthe terminal bronchioles and alveoli of lungs, and convert inthe pathogenicyeast phase.These fungalelementsgrow withinmacrophages until cellular immunity has been activated.Like M. tuberculosis  , H. capsulatum  can establish a latentstate within the confines of granulomas. The organismspresumably remain dormant until the host response becomesimpaired either by immunosuppressive agents or byco-morbid conditions such as acquired immunodeficiencysyndrome. Although reactivation histoplasmosis has beendocumented, it is often difficult to distinguish reactivationfrom re-infection in endemic areas. In the last few years, oneof the major risk factors for the appearance of progressivehistoplasmosis has been the use of antagonists of TNF- a inhumans (Lee et al  ., 2002; Wood et al  ., 2003). Thus,histoplasmosis in patients receiving mAb to this cytokinehas been the subject of numerous reports. In the followingparagraphs, a review of the immunoregulatory properties of TNF- a as they pertain to H. capsulatum  will be discussed. EFFECT OF NEUTRALIZATION OF TNF- a IN PRIMARYINFECTION After infection of mice with H. capsulatum  yeast cells, thereis a prompt and brisk induction of TNF- a generation (Smith et al  ., 1990; Wu-Hsieh et al  ., 1992). An increase in acytokine does not necessarily indicate that the cytokine isinvolved in host defenses. Several groups used eitherpolyclonal or mAb to TNF- a to neutralize endogenouscytokine. In both primary and secondary infections, neutra-lization of this cytokine leads to a progressive infection andsubsequent death of the animals (Smith et al  ., 1990;Wu-Hsieh et al  ., 1992; Allendoerfer and Deepe, 1998; Zhouet al., 1998). Thus, TNF- a serves as a bridge from innate toadaptive immunity. Moreover, once adaptive immunity has 34 Journal of Investigative Dermatology Symposium Proceedings (2007), Volume 12 & 2007 The Society for Investigative Dermatology Received 25 August 2006; accepted 19 September 2006  1 Division of Infectious Diseases, Veterans Affairs Hospital, University of Cincinnati College of Medicine, Cincinnati, Ohio, USACorrespondence: Dr George S. Deepe Jr, Division of Infectious Diseases, Veterans Affairs Hospital, University of Cincinnati College of Medicine, Cincinnati,Ohio 45267, USA. E-mail: george.deepe@uc.edu Abbreviations: TNF, tumor necrosis factor; TNFR, tumor necrosis factor receptor   been imprinted, TNF- a is required for its maintenance in theface of a re-challenge with H. capsulatum  .All of the preceding studies studied the effect of TNF- a neutralization at the time of infection. This approach does notaddress if this cytokine is necessary after infection has beenestablished. In primary infection, neutralization of thiscytokine as late as day 5 after infection with a non-lethalinoculum produced a high rate of mortality in mice.Neutralizing TNF- a on day 7 of infection when cellularimmunity is activated dampened the host response transientlybut did not lead to an uncontrolled infection. (Deepe andGibbons, 2006).The defects in immunity associated with the absence of this cytokine remain to be clarified. Two defects have beenuncovered in primary infection. In mice given neutrali-zing mAb to TNF- a , there is a sharp reduction in theproduction of nitric oxide. This nitrogen intermediate hasbeen shown to be necessary for the expression of protectiveimmunity in primary but not secondary infection (Lane et al  ., 1994; Zhou et al  ., 1995). Interestingly, neutralizationof TNF- a did not alter production of IFN- g although othershave reported that production of these two cytokines may beinterdependent (Allendoerfer and Deepe, 1998). A seconddefect is that T cells from mice infected with H. capsulatum  and given mAb cannot transfer protective immunity intomice lacking ab T cells whereas T cells from infectedanimals given rat IgG can. Thus, the absence or deficiency of TNF- a does alter the protective effect by T cells. Thedysfunction of the T cells from mice lacking TNF- a is notassociated with fewer IFN- g T cells or alterations in theability of these cells to traffic properly (Deepe and Gibbons,2006).TNF- a is proinflammatory cytokine. Thus, one wouldexpect that neutralization would diminish the number of inflammatory cells within the lungs of mice infected with H. capsulatum. However, recovery of cells from the lungs of mice infected with H. capsulatum  and given mAb to TNF- a demonstrates no major alterations; in fact, recovery of cells isincreased (Allendoerfer and Deepe, 1998). EFFECT OF TNF- a NEUTRALIZATION IN SECONDARYHISTOPLASMOSIS Neutralization of TNF- a in mice with secondary histoplas-mosis produces a different set of immunological disturbances.There is upregulation in the production of IL-4 and -10, twocytokines that are known to diminish protective immunity tothis fungus (Allendoerfer and Deepe, 1998). Neutralization of both, but not each alone, promotes the restoration of protective immunity. T cells from infected mice given mAbto TNF- a are incapable of transferring protection as was thecase with T cells from anti-TNF- a -treated mice with primaryhistoplamosis. Treatment of mice with anti-TNF- a antibodyon the day of infection or day 3 post-infection abolishedprotective immunity. When the antibody was given on day 5post-infection, there was an impact on fungal burden but noton the eventual survival of mice (Deepe and Gibbons, 2006).The finding that TNF- a neutralization in both primary andsecondary histoplasmosis induces T cells that cannot transferprotection requires an explanation. One possibility is that adeficiency of this cytokine leads to defective T cells.However, as assessed by CD69 they were capable of beingactivated. There was a significant decrease in the number of memory T cells in mice given mAb to TNF- a . These cells maybe the effector cells that deliver the signals that lead toprotection. However, their ability to produce IFN- g was notdiminished. Another possibility is that the absence of TNF- a isassociated with the generation of regulatory T cells. Supportfor this argument comes from two studies. In non-obesediabetic mice, neutralization of endogenous TNF- a increasesthe number and the activity of regulatory T cells. This cellpopulation is known to dampen or suppress cellularimmunity. Administration of recombinant cytokine leads toa decrement in number and function of these cells (Wu et al  .,2002). In a separate study, treatment of rheumatoid arthritispatients with infliximab, the mAb to TNF- a for humans, isassociated with an increase in the number and functionalproperties of regulatory T cells (Ehrenstein et al  ., 2004). Thus,the salutary effect of infliximab may be explained in part onthe generation of this cell population, which inhibitsinflammation. Although dampening cellular immunity maybe beneficial for inflammatory diseases, it may enhancesusceptibility to pathogenic microbes, especially those thatare intracellular. In this regard, we are currently exploringwhether treatment with mAb to TNF- a in mice is accom-panied by the emergence of regulatory T cells in the lungs of  H. capsulatum  -infected mice. TNFR KNOCKOUT MICE Signaling of TNF- a occurs through two receptors, and thedownstream effects of engaging one or another may overlap,although distinct functions can be ascribed to binding one orthe other receptor. Mice lacking either TNFR1 or TNFR2are susceptible to primary infection with 2 Â 10 6 yeasts of  H. capsulatum  but mice lacking TNFR2 are more resistant tosmaller inocula. The major immunological defect in TNFR1 À  /  À mice is a paucity of inflammatory cells within lungs. Onepossibility to explain these findings is that the absence of TNFR1 alters chemokine generation. In TNFR2 À  /  À mice, wefound a profound deficiency in IFN- g , and treatment of thelatter with recombinant cytokine restored protective immu-nity. In neither TNFR1 nor TNFR2 mice did we find adeficiency of nitric oxide (Allendoerfer and Deepe, 2000).These findings differed from those found in mice thatreceived anti-TNF- a mAb. Although the central disturbanceof each of these experiments was TNF- a and its signaling, theresults highlight the sharp biological disparities amongantibody neutralization and failure to signal through one of the receptors.In secondary histoplasmosis, antagonizing TNFR1 engage-ment using a blocking antibody alters handling of  H. capsulatum  in secondary infection. The reason for usinga blocking antibody rather than TNFR1 À  /  À mice is that thelatter do not survive a low dose of the fungus even withpotent antifungal treatment (Allendoerfer and Deepe, 2000)Thus, we had to resort to using a blocking antibody ratherthan the knockout mice. www.jidonline.org 35 GS Deepe Jr  TNF- a and Host Resistance to H. capsulatum   HISTOPLASMOSIS IN HUMANS RECEIVING TNF- a ANTAGONISTS Post-marketing surveillance for the TNF- a antagonists hasstrongly suggested that disseminated histoplasmosis is a riskfactor in patients receiving these agents although an absoluterisk value cannot be assigned. The mechanisms that lead tothe emergence or the re-emergence of the fungus have onlyrecently begun to be investigated. In vitro  , infliximabmodestly enhances intracellular growth of yeast cells, butdepresses proliferation of peripheral blood lymphocytes fromhealthy subjects to H. capsulatum  only when alveolarmacrophages were used as antigen-presenting cells (Wood et al  ., 2003). If macrophages or dendritic cells are used asantigen-presenting cells then the effect is not seen (Hage et al  ., 2005). These results have been interpreted to suggestthat the effect of infliximab is compartmentalized to thealveolar macrophage. This mAb also suppresses productionof IFN- g by either monocytes or alveolar macrophages fromhealthy subjects.One of the difficulties for clinicians is determining whowill develop histoplasmosis in those given TNF- a antagonists.At present, no skin test reagent is commercially available toscreen patients for the presence of exposure to H. capsula- tum  . Chest X-rays may demonstrate calcified lesions con-sistent with granulomas, but these may be a result of eithertuberculosis or histoplasmosis. The risk of developinghistoplasmosis in patients with X-rays consistent withgranulomas has not been determined. Thus, the presenceon chest X-ray of the calcified lesions should alert physiciansto the possibility that reactivation histoplasmosis may occur.The onset of a new intercurrent illness suggestive of thisfungal infection should prompt immediate evaluation and if necessary, treatment. SUMMARY The accumulated evidence both in experimental animals andin humans indicates that TNF- a is a critical factor in hostresistance to H. capsulatum  . The focus of the current work inmice has been to uncover the mechanisms by which thiscytokine exerts its functional properties. Less has been donein humans because the number of cases, while increased, isnot large. As it is possible that the response in humans maydiffer from that in mice, studies aimed at addressing theseissues in humans is imperative. CONFLICT OF INTEREST Dr George S. Deepe has received an honorarium to support production of thispaper, and has been a consultant for Amgen Inc. REFERENCES Aggarwal BB (2003) Signalling pathways of the TNF superfamily: a double-edged sword. Nat Rev Immunol  3:745–56Allendoerfer R, Deepe Jr GS (1998) Blockade of endogenous TNF- a exacerbates primary and secondary pulmonary histoplasmosis bydifferential mechanisms. J Immunol  160:6072–82Allendoerfer R, Deepe Jr GS (2000) Regulation of infection with Histoplasmacapsulatum  by TNFR1 and -2. J Immunol  165:2657–64Beutler B, Cerami A (1989) The biology of cachectin/TNF – a primarymediator of the host response. Annu Rev Immunol  7:625–55Botha T, Ryffel B (2003) Reactivation of latent tuberculosis infection in TNF-deficient mice. 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Proc Natl Acad Sci USA 99:12287–92 36 Journal of Investigative Dermatology Symposium Proceedings (2007), Volume 12 GS Deepe Jr  TNF- a and Host Resistance to H. capsulatum   Wu-Hsieh BA, Lee GS, Franco M, Hofman FM (1992) Early activation of splenic macrophages by tumor necrosis factor alpha is important indetermining the outcome of experimental histoplasmosis in mice. Infect Immun  60:4230–8Zhou P, Miller G, Seder RA (1998) Factors involved in regulating primary andsecondary immunity to infection with Histoplasma capsulatum  : TNF- a plays a critical role in maintaining secondary immunity in the absence of IFN- g . J Immunol  160:1359–68Zhou P, Sieve MC, Bennett J, Kwon-Chung KJ, Tewari RP, Gazzinelli RT et al. (1995) IL-12 prevents mortality in mice infected with Histo- plasma capsulatum  through induction of IFN- g . J Immunol  155:785–795 www.jidonline.org 37 GS Deepe Jr  TNF- a and Host Resistance to H. capsulatum 
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