Immunovirology - student projects

Arthritis caused by chikungunya virus

Chikungunya virus (CHIKV) is a mosquito borne alphavirus, related to Ross River virus, that has caused periodic outbreaks of predominantly rheumatic disease in Africa and Asia. "Chikungunya" is derived from the Makonde language (Tanzania) and means "that which bends up", referring to the joint-pain-induced posture of afflicted individuals.

Recently the largest documented outbreak of CHIKV disease occurred in the Indian Ocean islands and India during 2004-2007. Over 260,000 cases (one third of the population) were reported in Reunion Island (France) with 1.39 million cases in India and a small outbreak of 200 cases also occurring in Italy. CHIKV has been declared a high priority pathogen by the NIH (USA) and is a PC3 organism. No licensed vaccine or particularly effective drug is available for human use for any alphavirus.

We have recently developed the first adult wild type mouse model of CHIKV arthritis, which we now hope to exploit to answer some fundamental questions about the mechanisms (cytokines, chemokines, viral evasion of host responses, viral induction of cell death etc) that cause arthritis and the factors used by the mouse ultimately to cure the disease.

Understanding these processes will also have important implications for treatment of autoimmune arthritides like rheumatoid arthritis. Array technology, knockout mouse strains, and a series of immunological techniques will be applied to the problem. Ultimately the model will be used to test new prophylactic (eg vaccines) and therapeutic interventions.

The undecided Serpin

SerpinB2, also known as plasminogen activator inhibitor type-2 (PAI-2), is one of the most abundantly expressed proteins in differentiating keratinocytes (4-7 percent of total protein) and activated monocyte/macrophages (1-2 percent of total protein). It is expressed at nearly all sites of inflammation and inappropriate expression is associated with a number of diseases including pre-eclampsia, asthma, periodontal disease and cancer.

SerpinB2 is a member of the Clade B or ovalbumin-like serine protease inhibitor (ov-serpin) subgroup of the serpin superfamily, which includes proteinase inhibitor 6, 8 & 9, MENT, Bomapin and maspin. SerpinB2 is well described as an inhibitor of the extracellular urokinase plasminogen activator (uPA), with SerpinB2 able to inhibit uPA in vitro. Unfortunately, evidence that this represents the major physiological role of SerpinB2 in vivo is not compelling. SerpinB2-/- mice show no defect in the plasminogen activation system, and the double knockout PAI-1-/-/SerpinB2-/- animals show no additional defect in plasminogen activation over PAI-1-/- mice.

A bewildering array of functions for SerpinB2 have been reported; with the true physiological role of SerpinB2 entirely unclear. We have recently generated for the first time a fully backcrossed SerpinB2 knockout mouse, which we are exploiting to understand the physiological role of SerpinB2.

Recent experiments have illustrated that SerpinB2 expression in macrophages regulates the Th1 bias of antibody and T cells responses. This entirely novel observation begins to explain the clinical findings for SerpinB2 expression and has opened up an entire area for research. Using a number of molecular, biochemical and immunological techniques we hope to unravel the exact molecular mechanism whereby SerpinB2 expression leads to suppression of inflammatory cytokine release from activated macrophages.