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Wednesday, October 10, 2007

Migrations influenced immune evolution

An important component of the innate immune system evolved differently in different human populations, depending on the infectious diseases that each population has encountered, suggests a study published online this week in the Proceedings of the National Academy of Sciences. The authors found that variants of an immune receptor protect against bacterial infection in Europeans and Asians, while Africans often possess a version of the receptor that protects against malaria.

"Our study demonstrates that during migration out of Africa, the immune system has been changed by the infections it has encountered," senior author Mihai Netea of Radboud University Nijmegen Medical Center in the Netherlands told The Scientist in an Email.

Toll-like receptors (TLRs) defend hosts by recognizing molecules that all pathogens possess. One of these receptors, TLR4, protects against Gram-negative bacteria, mycobacteria, fungi, and malaria parasites.

Previous work has identified two common single nucleotide polymorphisms (SNPs) in TLR4, which appear to change the receptor's activity and alter susceptibility to infectious diseases. Different human populations also show different frequencies of these two SNPs.

To see if infectious disease pressures could have influenced TLR4's evolution in different human populations, researchers led by Bart Ferwerda, also of Radboud, analyzed TLR4 polymorphisms in individuals from Africa, Eurasia, and the Americas.

They found a high frequency of one of the SNPs in Africans, while Europeans showed high frequencies of both SNPs. The two SNPs appeared to cosegregate in European populations: people with one SNP always had the other. Most Asians and Americans showed neither SNP, instead expressing the ancestral alleles.

It was a bit of a surprise to find no Europeans with the single SNP found in Africans, Betea said, but it indicated "a strong evolutionary pressure."

The researchers next looked for functional differences between the TLR4 variant with one SNP, common among Africans, and the TLR4 variant with both SNPs, common among Europeans. They found that the African variant caused cells to produce high levels of a proinflammatory factor, while the European variant did not differ functionally from the ancestral TLR4.

The second SNP found in Europeans must somehow neutralize the proinflammatory effects of the first SNP, according to Igor Mokrousov of St. Petersburg Pasteur Institute in Russia, who was not involved in the work.

Other work has shown that enhanced inflammatory responses can contribute to death from septic shock, and the authors propose that this may explain why most populations do not possess the single SNP that leads to inflammation.

In Africa, however, the threat of malaria may have overridden the threat of bacterial infection. Previous research has suggested that people with the single SNP suffer lower mortality rates from malaria than do people with ancestral alleles, although the mechanism of this protection is unknown.

According to Calogero Caruso of the University of Palermo in Italy, the authors' hypothesis that malaria shaped TLR4 variants is "not completely convincing," because malaria was present in places other than sub-Saharan Africa during much of human history. Also, studies have conflicting findings on the role of inflammation in bacterial infection, said Caruso, who was not involved in the word. "Too much inflammation is dangerous as well as not enough inflammation, depending on the kind of bacteria and the individual phenotype."

"The interplay is very complex as [other] environmental factors also played a role" in shaping humans' immune evolution, Mokrousov told The Scientist. But the study presents "very interesting, exciting results," he said. "Pressure from infectious diseases was one of the forces that shaped the human immune system."

Melissa Lee Phillips

Links within this article:

C. Holding, "Evolution of innate immunity," The Scientist, July 8, 2004.

B. Ferwerda et al., "TLR4 polymorphisms, infectious diseases, and evolutionary pressure during migration of modern humans," PNAS, published online October 8, 2007.

M. Goozner, "Beating malaria," The Scientist, December 1, 2006.

K.Y. Kreeger, "Taking toll of Toll-like receptors," The Scientist, May 5, 2003.

S. Akira, K. Takeda, "Toll-like receptor signalling," Nature Reviews Immunology, July 2004.

B. Beutler, "Tlr4: central component of the sole mammalian LPS sensor," Current Opinion Immunology, February 2000

N.C. Arbour et al., "TLR4 mutations are associated with endotoxin hyporesponsiveness in humans," Nature Genetics, June 2000.

M.J. Newport et al., "The toll-like receptor 4 Asp299Gly variant: no influence on LPS responsiveness or susceptibility to pulmonary tuberculosis in The Gambia," Tuberculosis (Edinburgh), 2004.

B. Beutler, A. Cerami, "Cachectin and tumour necrosis factor as two sides of the same biological coin," Nature, April 17, 1986.

F.P. Mockenhaupt et al., "Toll-like receptor (TLR) polymorphisms in African children: Common TLR-4 variants predispose to severe malaria," PNAS, January 3, 2006.

Calogero Caruso

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