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Cell-mediated cytotoxicity in recovery from poxvirus infections
1Division of Immunology and Genetics, John Curtin School of Medical Research, Australian National University, PO Box 334, Canberra, ACT 2601, Australia. arno.mullbacher@anu.edu.au
Abstract:
The availability of mutant and gene targeted knockout mice with defects in components of cellular cytotoxicity mediated by either the Fas or the exocytosis pathway permitted an analysis of their role in recovery from poxvirus infections. Ectromelia (EV), a natural mouse pathogen causing mousepox, the closely related orthopoxviruses cow pox (CPV) and vaccinia virus (VV), each encode serpins that inhibit Fas mediated apoptosis and lysis of target cells. Nevertheless, distinct differences were seen when the three viruses were inoculated into perforin-deficient mice: highly resistant C57Bl/6 mice became susceptible to low doses of EV; resistance to CPV increased whereas there was no effect on VV infections. Absence of the cytolytic granule associated granzymes (gzm) A and B rendered C57Bl/6 mice increasingly more susceptible to EV infections. Lack of both gzms rendered them as susceptible as perforin deficient mice, despite the presence of functionally active perforin. Elevated EV titres in liver and spleen of gzmA x B deficient mice, early after infection and before cytotoxic T cells were detectable, strongly suggests that these two gzms exert an antiviral effect by a mechanism distinct from effector molecules of NK and cytotoxic T cells.
Insights
Cellular cytotoxicity, involving Fas and exocytosis pathways, plays a key role in poxvirus recovery. Granzymes A and B offer early antiviral defense against Ectromelia virus, independent of cytotoxic T cells.
Area of Science:
- Immunology
- Virology
- Cellular Biology
Background:
- Poxviruses like Ectromelia (EV), Cowpox (CPV), and Vaccinia (VV) encode serpins inhibiting Fas-mediated apoptosis.
- Cellular cytotoxicity pathways, including Fas and exocytosis, are crucial for host defense against viral infections.
Purpose of the Study:
- To investigate the roles of Fas and exocytosis pathways in poxvirus infection recovery using gene-targeted knockout mice.
- To elucidate the specific contributions of perforin and granzymes A/B in defense against Ectromelia virus.
Main Methods:
- Analysis of poxvirus infections (EV, CPV, VV) in perforin-deficient and granzyme A/B-deficient mice.
- Assessment of viral titers in liver and spleen at various infection stages.
- Evaluation of mouse susceptibility to different poxvirus strains.
Main Results:
- Perforin deficiency differentially affected susceptibility to EV, CPV, and VV, with increased susceptibility to EV in C57Bl/6 mice.
- Granzyme A and B deficiency significantly increased susceptibility to EV, comparable to perforin deficiency.
- Elevated EV titers in granzyme A/B deficient mice early in infection suggest a non-T cell mediated antiviral mechanism.
Conclusions:
- Granzymes A and B provide crucial early antiviral protection against Ectromelia virus, acting through a mechanism independent of cytotoxic T cells.
- Cellular cytotoxicity components, particularly granzymes, are vital for effective host defense against poxvirus infections.