AsianScientist (Feb. 22, 2016) – Researchers from India have shown that immune cells make use of cholesterol-rich domains called lipid rafts to transport pathogens to the cell center where they are destroyed. Their findings, published in Cell, could be key to developing treatments against infectious diseases.
The cells of our immune system kill pathogens by enclosing them in a compartment called the phagosome. The phagosome undergoes programmed maturation, which degrades the pathogen. Closely linked to this degradation is active transport of the phagosome inside cells by nanoscale ‘motor’ proteins such as dynein and kinesin, which are force generators for many kinds of biological movements.
Phagosomes carried by the motors initially move in a back-and-forth manner near the cell periphery, and mature by fusing with other compartments. As time passes, there is a ‘switch’ that causes the phagosomes to move in an almost unidirectional manner towards the cell center. There, they fuse with acidic lysosomes so that the pathogen can be destroyed.
Researchers at the Tata Institute of Fundamental Research have found that the ‘switch’ in a phagosome’s destination is because of the formation of cholesterol-rich domains called lipid rafts on the phagosome membrane.
This switch in motion is important for the degradation of pathogens, as has been observed in the case of Mycobacterium tuberculosis and Salmonella, both of which abort this switch as a strategy for survival and infection.
“We have found the transport of pathogens to lysosomes is achieved by the physical clustering of many nanoscale dynein motors,” says lead author Professor Roop Mallik.
Dynein motors cluster into these lipid raft domains, and by doing so, are able to work cooperatively in large teams. This cholesterol-induced assembly of dynein teams transports the phagosome towards acidic lysosomes for degradation.
Importantly, they also showed that a lipid molecule from the parasite Leishmania donovani is able to disrupt the clustering of dynein, and therefore prevent the transport of phagosomes towards lysosomes. Leishmania causes visceral leishmaniasis or Kala-azar, a deadly disease endemic to many tropical countries, including India.
The lipid-driven disruption of dyenin may be a mechanism by which Leishmania can spread infection by surviving and multiplying inside the immune cells of our liver and spleen, the scientists said.
“This discovery may help devise treatment strategies against such dangerous infections. These results are also very relevant to the pathogens that cause tuberculosis and typhoid. Our work also shows how the much-hated molecule, cholesterol, can be useful in clearing infections,” said Mallik.
The article can be found at: Rai et al. (2016) Dynein Clusters into Lipid Microdomains on Phagosomes to Drive Rapid Transport toward Lysosomes.
Source: Tata Institute of Fundamental Research; Photo: Shutterstock.
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