Effect of Invasive Aspergillosis Infection on the Immune Responses of Cancer Mice

Document Type: Original Article


1 Mycology Research Centre, Faculty of Veterinary Medicine, Tehran University, Tehran, Iran

2 Immunology Department, School of Medicine, Tarbiat Modares University, Tehran, Iran

3 Immunology Department, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran

4 Biotechnology Department, Razi Vaccine and Serum Research Institute, Tehran, Iran


Using a cancer murine model of invasive aspergillosis (IA), we investigated the expression of TLR-2, Dectin-1 and the level of cytokine production by CD4+ T helper cells in different groups of mice (with or without cancer), also, the effect of invasive aspergillosis on the immune response pattern of cancer mice.
Materials and Methods
Patterns of susceptibility and resistance to infection obtained with different groups of mice injected with Aspergillus fumigatusconidia. TLR-2 and Dectin-1 analyzed applying flowcytometry and cytokine production of cultured splenocytes by ELISA method.
Cancer mice that challenged with A. fumigatus conidia showed significant increase in TLR-2 and Dectin-1 levels compared with the two other control groups (normal mice challenged with A. fumigatus and                 non-infected cancer mice). Moreover, it showed insignificant decrease in IFN-γ and IL-10 levels and insignificant increase in TNF-α level. The data demonstrated remarkable rise in IL-4 level and the mortality of cancer mice that intravenously infected with A. fumigatus.
Probably IA causes stimulation in innate immunity and Th2 cells, also some disorganization in cytokine production in CD4+ T helper cells. We hypothesize that concomitance of IA and cancer may change the microenvironment for local or systemic immune responses. Other complementary studies could help supporting our hypothesis.


1.Bodey GPS. Vartivarian aspergillosis. Eur J Clin Microbiol Infect Dis 1989:8:413-437.

2. Rinaldi MG. Invasive aspergillosis. Rev Infect Dis 1983:5:1061-1077.

3.Soubani AO, Chandrasekar PH. The clinical spectrum of pulmonary aspergillosis. Chest 2002; 121:988-999.

4.Segal BH, Walsh TJ. Current approaches to diagnosis and treatment of invasive aspergillosis. Am J Respir Crit Care Med 2005; 173:707-717.

5.Perlroth J, Choi B, Spellberg B. Nosocomial fungal infections: epidemiology, diagnosis and treatment. Med Mycol 2007; 45:321-346.

6.Pollock JD, Williams DA, Gifford MA, Li L L, Du XJ, Fisherman,S, et al. Mouse model of X-linked chronic granulomatous disease, an inherited defect in phagocyte superoxide production. Nat Genet 1995; 9:202-209.

7.Schaffner A, Douglas H, Braude A. Selective protection against conidia by mononuclear and against mycelia by polymorphonuclear phagocytesin resistance to Aspergillus: observations on these two lines of defense in vivo and in vitro with human and mouse phagocytes. J Clin Invest 1982; 69:617–631.

8.De Repentigny L, Petitbois S, Boushira M, Michaliszyn E, Senechal S, Gendron N, et al. Acquired immunity in experimental murine aspergillosis is mediated by macrophages. Infect Immun 1993:61:3791-3802.

9.Rivera A, Hohl T, Pamer EG. Immune responses to Aspergillus fumigatus infections. Biol Blood Marrow Transplant  2006; 12:47-49.

10.Dixon DM, Polak A, Walsh TJ. Fungus dose-dependent primary pulmonary aspergillosis in immunosuppressed mice. Infect Immun 1989; 75:1452-1456.

11.Gersuk GM, Underhill DM, Zhu L, Marr KA. Dectin-1 and TLRs Permit macrophages to distinguish between different Aspergillus fumigatus cellular states. J Immunol 2006; 176:3717-3724.

12.Segal BH. Role of macrophages in host defense against aspergillosis and strategies for immune augmentation. Oncologist 2007; 12:7-13.

13.Romani L. Immunity to fungal infections. Nat Rev Immunol 2004; 4:1-23.

14.Gantner BN, Simmons RM, Canavera SJ, Akira S,Underhill DM. Collaborative induction of inflammatory responses by Dectin-1 and Toll-like receptor 2. J Exp Med 2003; 197:1107-1117.

15.Knutsen AP, Mueller KR, Levine AD, Chouhan B, Hutcheson PS, Slavin RG. Asp f I CD4+ TH2-like T-cell lines in allergic bronchopulmonary aspergillosis. J Allergy Clin Immunol 1994: 94:215–221.

16.Kurup VP, Choi H, Murali PS, Coffman RL.  IgE and eosinophil regulation in a murine model of allergic aspergillosis. J Leukoc Biol 1994; 56: 593–598.

17.Kurup VP, Mauze S, Choi H, Seymour BW, Coffman RL. A murine model of allergic bronchopulmonary aspergillosis with elevated eosinophils and IgE. J Immunol 1992; 148:3783–3788.

18.Murali PS, Dai G, Kumar A, Fink JN, Kurup VP. Aspergillus antigen induced eosinophil differentiation in a murine model. Infect Immun 1992; 60:1952–1956.

19.Nagai H, Guo J, Choi H, Kurup V. Interferon-γ and tumornecrosis factor-α protect mice from invasive aspergillosis. J Infect Dis 1995; 172:1554–1560.

20.Lehmann PF, White LO. Acquired immunity to Aspergillus fumigatus. Infect Immun 1976; 13:1296–1298.

21.Karuna S. Verma, Vidhan Jain, Rathore AS. Role of Aspergillus spp. in causing possible nosocomial aspergillosis among immunocompromised cancer patients. Ind J Allergy Asthma Immunol 2003; 17:77-83.

22.Bellocchio S, Montagnoli C, Bozza S, Gaziano R, Rossi G, Mambula SS, et al. The contribution of the Toll-like/IL-1 receptor superfamily to innate and adaptive immunity to fungal pathogens in vivo. J Immunol  2004;172:3059–3069.

23.Netea MG, Warris A, Van der Meer JW , Fenton MJ, Verver-Janssen TJ, Jacobs LE, et al. Aspergilus fumigatus evades immune recognition during germination through loss of Toll-like receptor-4 mediated signal transduction. J Infect Dis 2003; 188:320–326.

24.Meier A, Kirschning CJ, Nikolaus T, Wagner H, Heesemann J, Ebel F. Toll-like receptor (TLR) 2 and TLR4 are essential for Aspergillus-induced activation of murine macrophages. Cell Microbial 2003; 5:561-570.

25.Netea MG, Warris A, Van der Meer JWM, Fenton MJ, Verver-Janssen TJG, Jacobs LEH, Andresen T, Verweij PE, Kullberg BJ. Aspergillus fumigatus evades immune recognition during germination through loss of Toll like receptor-4-mediated signal transduction. J Infect Dis 2003; 188:320-326.

26.Brown GD, Herre J, Williams DL, Willment JA, Marshall ASJ, Gordon S. Dectin-1 mediates the biological effects of beta-glucan. J Exp Med 2003; 197:1119-1124.

27.Mambula SS, Sau K, Henneke P, Golenbock DT, Levitz SM. Toll-like receptor (TLR) signaling in response to Aspergillus fumigatus. J Biol Chem 2002; 277:39320-3932.

28.Braedel S, Radsak M, Einsel H, Latgé JP, Michan A, Loeffler J, et al. Aspergillus fumigatus antigens activate innate immune cells via Toll-like receptors 2 and 4. Br J Haematol 2004; 125:392-399.

29.Flo TH, Halaas O, Lien E, Ryan L, Teti G, Golenbock DT, et al. Human toll-like receptor 2 mediates monocyte activation by Listeria monocytogenes, but not by group B Streptococci or lipopolysaccharide. J Immunol  2000;164:2064-2069.

30.Takeuchi O, Hoshino K, Kawai T, Sanjo H, Takada H, Ogawa T, et al. Differential roles of TLR2 and TLR4 in recognition of Gram-negative and Gram-positive bacterial cell wall components. Immunity 1999; 11:443-451.

31.Gosselin  D, Desanctis J, Boule M, Skamene E, Matouk C, Radzioch D, et al. Role of tumor necrosis factor alpha in innate resistance to mouse pulmonary infection with Pseudomonas aeruginosa. Infect  Immun 1995; 63:3272-3278.

32.Laichalk LL, Kunkel SL, Strieter RM, Danforth JM, Bailie MB, Standiford TJ. Tumor necrosis factor mediates lung antibacterial host defense in murine Klebsiella pneumonia. Infect Immun 1996; 64:5211-5218.

33.Cenci E, Perito S, Enssle  KH, Mosci P, Latgé JP,Romani L,et al.Th1 and Th2 cytokines in mice with invasive aspergillosis. Infect Immun 1997; 65:564-570.

34.Djeu JY. Modulators of immune responses to fungi. In: Murphy JW, Friedman H, Bendinelli M. editor. Fungal infections and immune responses. NewYork N.Y: Plenum Press; 1993. p. 521-532.

35.Palmer LB, Greenberg HE, Schiff M. Corticosteroid treatment as a risk factor for invasive aspergillosis in patients with lung disease. Thorax 1991; 46:15-20.