How herpesviruses win the footrace against the immune system
HZI researchers have identified a tool used by viruses to shut off the immune response
Bacteria and viruses continuously challenge the immune system. They reach the body by inhalation or via host contact with saliva, blood, or other secretions, but upon entry, the immune system recognises and fights these pathogens through a variety of mechanisms. In most cases, the immune system successfully brings the infection under control and eliminates the pathogen. However, one virus family is superbly adapted to the immune system and cannot be eliminated: the herpesviruses. Infection is for life. A research team at the Helmholtz Centre for Infection Research (HZI) has identified a herpesvirus protein that specifically shuts off the immune response, enabling the virus to establish lifelong infection in the body. The results have been published in the journal PLOS Pathogens.
Herpesviruses have coexisted with humans for millions of years, and during this time they have developed elegant strategies to escape immune system control. An important representative of the herpesvirus family is cytomegalovirus (CMV) – about half of the German population carries this virus. “Acute CMV infection of a woman during pregnancy is a huge danger for the infant in the womb. During pregnancy, CMV can be transmitted to the fetus and cause serious and lifelong damage including deafness and microcephaly,” says Prof Melanie Brinkmann, who has led the junior research group “Viral Immune Modulation” at the HZI since 2010. To date, no vaccine against CMV is available, in part because the mechanisms used by this virus to weaken the immune response are not fully understood. “To successfully fight CMV infection, we need a detailed understanding of the switches flipped by this virus to outsmart our immune system,” says Brinkmann.
As part of the Helmholtz Virtual Institute “Viral Strategies of Immune Evasion” (VISTRIE), the Brinkmann research group used an unbiased screen of CMV proteins to identify viral inhibitors of the immune response. They found a poorly characterised CMV protein that is able to incapacitate the antiviral immune response just a few minutes after infection. During infection, this protein, named M35, is introduced directly into a target host cell with the virus particle itself. In infected cells, it precisely controls the nucleus – the cellular control centre – where it blocks the antiviral immune response. By means of genetically modified viruses the researchers found in mice that the immune system is more adept at controlling CMV infection when M35 is absent from the virus particle.
“Our work shows that immediately after entry in the host species, CMV takes action to mitigate the immune response”, says Melanie Brinkmann. “It is a race against time that CMV unequivocally wins. We have shown that the M35 protein is essential for CMV to win this competition. Thus, it provides a crucial contribution to the strategy used by this virus to establish a lifelong infection in its host.” In collaboration with researchers at the HZI and the Hannover Medical School (MHH), Brinkmann’s team now plans to further characterise the mechanism of the M35 protein. In the future, specific inhibitors that block the function of M35 may become promising antiviral substances for the treatment of CMV infection.
B. Chan, V. Gonçalves Magalhães, N.A.W. Lemmermann, V. Juranić Lisnić, M. Stempel, K.A. Bussey, E. Reimer, J. Podlech, S. Lienenklaus, M.J. Reddehase, S. Jonjić, M.M. Brinkmann: The murine cytomegalovirus M35 protein antagonizes type I IFN induction downstream of pattern recognition receptors by targeting NF-κB mediated transcription. PLOS Pathogens, 2017, http://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1006382