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Kevin M Tyler

Publications and source records attributed to Kevin M Tyler.

7 recordsLinked to original sources
PubMed2005

Responsive microtubule dynamics promote cell invasion by Trypanosoma cruzi.

The American trypanosome, Trypanosoma cruzi, can invade non-phagocytic cell types by a G-protein-mediated, calcium-dependent mechanism, in which the cell's natural puncture repair mechanism is usurped in order to recruit lysosomes to the parasite/host cell junction or 'parasite synapse.' The fusion of lysosomes necessary for construction of the nascent parasitophorous vacuole is achieved by directed trafficking along microtubules. We demonstrate altered host cell microtubule dynamics during the initial stages of the entry process involving de novo microtubule polymerization from the cytoplasmic face of the parasite synapse which appears to serve as a secondary microtubule organizing centre. The net result of these dynamic changes to the host cell's microtubule cytoskeleton is the development of the necessary infrastructure for transport of lysosomes to the parasite synapse.

Animals↗
PubMed2005

Effects of cannabinoid treatment on Chagas disease pathogenesis: balancing inhibition of parasite invasion and immunosuppression.

Trypanosoma cruzi invades heart cells via a calcium-dependent, G protein-mediated mechanism, leading to severe cardiac inflammation considered by some to be autoimmune in nature. Cannabinoids inhibit calcium flux and G protein signalling; as potent immunosuppressive agents, they are effective in the treatment of autoimmune disease but contraindicated for the treatment of infections. We compared the action of the synthetic cannabinoid R(+)WIN55,212 and its inactive isomer S(-)WIN55,212 on cardiac myoblast invasion: R(+)WIN55,212 inhibited invasion by over 85%. We then tested for efficacy in modulating pathogenesis in mice by assaying parasite burden in heart and blood, cellular and humoral immunity to parasite and self antigens, and mortality. R(+)WIN55,212 significantly reduced cardiac inflammation but led to considerably increased parasitaemia. Cardiac parasitosis and mortality were not significantly different in treatment and control groups. We conclude that cannabinoids can block cardiac cell puncture repair mechanisms, thereby inhibiting trypanosome invasion as predicted by the mode of drug action, but, also inhibit immune cell effector functions, offsetting the benefit of inhibition parasite cell invasion. Refined use of cannabinoids may prove therapeutic in the future, but our results raise concern about the effect of cannabis use on those chronically infected by T. cruzi and on heart cell homeostasis generally.

Animals↗
PubMed2005

Novel antitrypanosomal agents.

Trypanosomes are the causative agents of Chagas' disease in Central and South America and sleeping sickness in sub-Saharan Africa. The current chemotherapy of the human trypanosomiases relies on only six drugs, five of which were developed > 30 years ago. In addition, these drugs display undesirable toxic side effects and the emergence of drug-resistant trypanosomes has been reported. Therefore, the development of new drugs in the treatment of Chagas' disease and sleeping sickness is urgently required. This article summarises the recent progress in identifying novel lead compounds for antitrypanosomal chemotherapy. Particular emphasis is placed on those agents showing promising, selective antitrypanosomal activity.

Animals↗
PubMed2003

Maintainence of parasitaemia - is it to die for?

One of the major differences between protozoan differentiation and metazoan differentiation is that protozoan cells normally retain potency during differentiation, which need not, therefore, be considered altruistic. Altruism does, however, arise at the level of the organism and consequently, protozoons have the potential to evolve altruistic traits. This is particularly true when, as with Trypanosoma brucei parasitaemias, populations are genetically homogeneous. This essay argues that whilst reports of altruistic phenomena during the trypanosome life cycle remain controversial, the prospect of reagents able to instigate pathways of cell death or differentiation bears further investigation.

Journal Article↗