Saturday, May 21, 2016

Why anti-viral immune serum doesn't work in every infected patient?

Many viruses, such as Ebola or avian-origin Flu viruses, are extremely virulent and can cause death of infected individuals within days. However, some individuals are naturally resistant to such virulent infections and generate protective, neutralizing antibodies in response to them. Many organizations across world responsible for public health safety [and also military institutions] try to stockpile such anti-viral sera obtained from individuals who survive natural infection. It is believed that injection of anti-viral serum into infected individuals could help them to survive.

However, new study in journal Nature suggests that anti-viral serum effectiveness depends on viral tropism. It turns out that protection against viruses that infect so called immune privileged tissues, such as brain tissue, required presence of both anti-viral neutralizing antibodies and anti-viral CD4 T cells. Specifically, the authors, led by Akiko Iwasaki from Yale School of Medicine, showed that anti-viral CD4 T cell's role is to open the "gate" to privileged tissues for anti-viral antibodies that usually can not cross such barrier on their own.

For this study the authors used herpes simplex virus type 2 (HSV-2) virus challenge model that infects mouse immune privileged tissues such as the innervating neurons in the dorsal root ganglia (DRG). Initially the authors reported and re-confirmed that if mice were vaccinated with attenuated strain of HSV-2 before WT virus challenge, then these vaccinated mice were protected against WT virus challenge and this protection depended on antibody.

Strangely, however, immune serum could not protect naive, non-vaccinated mice against WT virus challenge. Moreover, immune serum protected vaccinated mice even if these mice did not make antibodies on their own. This suggested that something else  besides antibodies [generated during vaccination] needed alongside with anti-viral antibodies for virus protection

Indeed, vaccinated mice depleted of anti-viral memory CD4 T cells just prior to WT virus challenge were not protected.

Next, the authors found that presence of anti-viral CD4 T cells (but not of irrelevant CD4 T cells) were necessary for anti-viral antibodies to enter and accumulate within infected neuronal tissue.

Finally, the authors showed that neuronal tissue recruitment of anti-viral CD4 T cells depended on α4β1 (VLA4 integrin) interactions and subsequent CD4 T cell-derived IFN-γ secretion mediated local vascular permeability to enable antibody access to neuronal tissue.

In summary, this study explains why simple application of immune serum is not always sufficient for protection against neurotropic infections. Neutralizing immune serum on its own is not able to penetrate barrier, immune privileged tissues in infected recipients if they lack anti-viral CD4 T cells. This could explain why anti-Ebola serum was not effective in all Ebola-infected patients. This study also provides mechanistic explanation for current paradigm for rabies virus protection that requires application of both vaccine [to induce T cells] alongside anti-rabies immune serum.

David Usharauli

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