Microbiota regulates immune defense against respiratory tract influenza A virus infection

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PNAS


Microbiota regulates immune defense against respiratory tract influenza A virus infection

Takeshi Ichinohea,b,1,
Iris K. Panga,1,
Yosuke Kumamotoa,
David R. Peaperc,
John H. Hoa,
Thomas S. Murrayc,d, and
Akiko Iwasakia,2

aDepartment of Immunobiology,
dDepartment of Pediatrics, and
cLaboratory Medicine, Yale University School of Medicine, New Haven, CT 06520; and
bDepartment of Virology, Faculty of Medicine, Kyushu University, Fukuoka 812-8582, Japan

Edited by Dan R. Littman, New York University Medical Center, New York, NY, and approved February 7, 2011 (received for review December 23, 2010)

Abstract

Although commensal bacteria are crucial in maintaining immune homeostasis of the intestine, the role of commensal bacteria in immune responses at other mucosal surfaces remains less clear. Here, we show that commensal microbiota composition critically regulates the generation of virus-specific CD4 and CD8 T cells and antibody responses following respiratory influenza virus infection. By using various antibiotic treatments, we found that neomycin-sensitive bacteria are associated with the induction of productive immune responses in the lung. Local or distal injection of Toll-like receptor (TLR) ligands could rescue the immune impairment in the antibiotic-treated mice. Intact microbiota provided signals leading to the expression of mRNA for pro?IL-1β and pro?IL-18 at steady state. Following influenza virus infection, inflammasome activation led to migration of dendritic cells (DCs) from the lung to the draining lymph node and T-cell priming. Our results reveal the importance of commensal microbiota in regulating immunity in the respiratory mucosa through the proper activation of inflammasomes.

http://www.pnas.org/content/early/2011/03/07/1019378108.short

 

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Re: Microbiota regulates immune defense against respiratory tract influenza A virus infection

Gut microbes influence defense against influenza
Virology Blog

The bacteria in our intestines outnumber by tenfold the 100 trillion cells that comprise the human body. This gut microbiota has many beneficial functions, including the production of vitamins and hormones, fermentation, regulation of gut development, and shaping intestinal immune responses. They also play a role in pathological conditions such as diabetes and obesity, and influence the immune functions of distal mucosal surfaces such as the lung. Examples include the amelioration of allergen-induced asthma by colonization of the stomach with Helicobacter pylori, and involvement of the gut microbiota in development of immune defenses against influenza virus infection.

When the gut microbiome of mice is altered by treatment with antibiotics, subsequent intranasal infection with influenza A virus leads to reduced antiviral antibody and T-cell responses. The antibiotic treatment does not cause a general immunodeficiency – the mice can respond normally to protein antigens.

The defective immune response to influenza virus in antibiotic treated mice can be rescued by treating the mice with compounds that stimulate the innate immune response – such as lipopolysaccharide, a bacterial product. These compounds rescue the immune defect when administered either intransally or rectally at the time of influenza virus infection. Apparently stimulating the innate immmune response in the gut is sufficient to correct an immune defect in the lung.

How might gut bacteria be important for immune responses to a lung infection? When influenza virus infects the lung, development of immune defenses depend upon a complex of several proteins called the inflammasome. This structure is needed for the production of cytokines that promote adaptive immune defenses: antibodies and T cells. These cytokines are also needed for the activity of dendritic cells, sentinels that sense a virus infection, and travel to the nearby lymph nodes to inform T cells that there is a problem.

Antibiotic treatment of mice impairs the influenza virus-induced production of inflammasome-dependent cytokines. These results are consistent with the finding that antibiotic-treated mice respond normally to infection with herpes simplex virus type 2 and Legionella pneumophila, two pathogens for which the inflammasome is not required for adaptive immune responses. Furthermore, microbe-mediated inflammasome activation is needed for migration of lung dendritic cells to lymph nodes. In antibiotic treated mice, lung dendritic cells fail to migrate to local lymph nodes. Hence T cells are not informed of the infection, leading to poor antibody and cellular responses.

These findings reveal a link between the gut microbial community and inflammasome-dependent activation of cytokines. How gut bacteria effect this process is not understood. One idea is that bacterial products stimulate white blood cells in the intestine to produce compounds that migrate to the lung and activate the inflammasome.

If you are wondering about the practical consequences of these findings, read the last paragraph of the paper:

Because antibiotic use is prevalent in the treatment of respiratory infections, our results imply a possible deleterious effect of such treatment in initiating proper immune responses to influenza virus. Conversely, it will be important to determine whether probiotic therapy can be explored for immune-stimulating effects during the flu season.

http://www.virology.ws/2011/09/06/gut-microbes-influence-defense-against-influenza/