The Walter and Eliza Hall Institute of Medical Research

Dr Marc Pellegrini

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Division: Infection and Immunity

Research Overview

Our immune system evolved to combat microbial attacks. In an effort to deal with an expansive landscape of pathogens the immune system is forever on guard, and can sometimes respond inappropriately, causing collateral damage and overt autoimmunity.

For this reason we evolved a complex network of inhibitory networks that only permit a full-blown immune response under conditions of bone fide infection. The consequence of this inhibition is that microorganisms can sabotage these networks to avoid being caught by the immune system.

Overwhelming infections like HIV, hepatitis B and C and tuberculosis use several diverse mechanisms to impair the immune response. A common theme in these infections is that high pathogen burden, and large amounts of pathogen-associated proteins, overwhelm rather than activate immune responses. The relative immunodeficient state that ensues allows pathogens to persist in the host.

The implications of our research are underscored by the burden of chronic infections. HIV, hepatitis B virus and hepatitis C virus are responsible for approximately four million deaths per year. More than two billion people have been infected with hepatitis B and one third of the world’s population is infected with Mycobacterium tuberculosis.

There is an urgent need to develop new therapies that focus on augmenting host immunity. Our research focuses on elucidating the mechanisms responsible for impaired immunity in chronic overwhelming infections and, importantly, identifying factors that can promote host immune responses and clear chronic infections.

Targeted and reversible inhibition of host immune regulatory networks offers a common therapeutic platform to treat diverse chronic overwhelming infections and these types of therapies would be refractory to traditional pathogen resistance mechanisms.

Research Interests

• Identifying host genes that abrogate immunity
• Testing therapeutic interventions in pre-clinical hepatitis B virus, HIV and tuberculosis infection
• Human epidemiological and human descriptive studies of tuberculosis and HIV infection

Selected Publications

1. Pellegrini M, Calzascia T, Toe JG, Preston SP, Lin AE, Elford AR, Shahinian A, Lang PA, Lang KS, Morre M, Assouline B, Lahl K, Sparwasser T, Tedder TF, Paik JH, DePinho RA, Basta S, Ohashi PS, Mak TW. IL-7 engages multiple mechanisms to overcome chronic viral infection and limit organ pathology. Cell. 2011 Feb 18; 144(4):601-13. Epub 2011 Feb 3. PMID: 21295337
2. Pellegrini M, Calzascia T, Elford AR, Shahinian A, Lin AE, Dissanayake D, Dhanji S, Nguyen LT, Gronski MA, Morre M, Assouline B, Lahl K, Sparwasser T, Ohashi PS, Mak TW. Adjuvant IL-7 antagonizes multiple cellular and molecular inhibitory networks to enhance immunotherapies. Nat Med. 2009 May; 15(5):528-36. Epub 2009 Apr 26. PMID: 19396174
3. Calzascia T*, Pellegrini M*, Lin A, Garza KM, Elford AR, Shahinian A, Ohashi PS,Mak TW. CD4 T cells, lymphopenia, and IL-7 in a multistep pathway to autoimmunity. Proc Natl Acad Sci USA. 2008 Feb 26; 105(8):2999-3004. Epub 2008 Feb 14. PMID: 18287017 *Equal contribution
4. Calzascia T, Pellegrini M, Hall H, Sabbagh L, Ono N, Elford AR, Mak TW, Ohashi PS. TNF-alpha is critical for antitumor but not antiviral T cell immunity inmice. J Clin Invest. 2007 Dec; 117(12): 3833-45. PubMed PMID: 179922585.
5. You H, Pellegrini M, Tsuchihara K, Yamamoto K, Hacker G, Erlacher M, Villunger A, Mak TW. FOXO3a-dependent regulation of Puma in response to cytokine/growth factor withdrawal. J Exp Med. 2006 Jul 10; 203(7):1657-63. Epub 2006 Jun 26. PMID: 16801400
6. Pellegrini M, Bath S, Marsden VS, Huang DC, Metcalf D, Harris AW, Strasser A. FADD and caspase-8 are required for cytokine-induced proliferation of hemopoieticprogenitor cells. Blood. 2005 Sep 1; 106(5):1581-9. Epub 2005 May 19. PMID: 15905188
7. Pellegrni M, Bouillet P, Robati M, Belz GT, Davey GM, Strasser A. Loss of Bim increases T cell production and function in interleukin 7 receptor-deficient mice. J Exp Med. 2004 Nov 1; 200(9):1189-95. Epub 2004 Oct 25. PMID: 15504823
8. Pellegrini M, Belz G, Bouillet P, Strasser A. Shutdown of an acute T cell immune response to viral infection is mediated by the proapoptotic Bcl-2 homology 3-only protein Bim. Proc Natl Acad Sci USA. 2003 Nov 25; 100(24):14175-80. Epub 2003 Nov 17. PMID: 14623954

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Current Laboratory Members

Faculty Member: Marc Pellegrini, MB BS BSc PhD Melb FRACP

Postdoctoral Fellow: Gregor Ebert, PhD Cologne

Research Assistant: Claire Bowtell, BSc Melb

Research Assistant: Simon Preston, BBiomedSci (Hons) Monash

Research Assistant: Hamish Scott, BMedRes (Hons) UTAS

Postgraduate Student: Jesse Toe, BSc (Hons) Melb