Cindy, Steph, and Vincent reveal that lymphocyte trafficking through lymph nodes and lymph is circadian – it is dependent on the time of day.
Become a patron of Immune!
Show notes at microbe.tv/immune
On episode #316 of the science show This Week in Virology, Vincent, Alan, Rich and Kathy discuss how interleukin 10 modulation of Th17 helper cells contributes to alphavirus pathogenesis.
You can find TWiV #316 at www.microbe.tv/twiv.
Influenza H5N1 virus frightens many because of the widely quoted case fatality ratio of >50%, which is based on the number of deaths among the fewer than 600 cases confirmed by the World Health Organization. Such fear is misguided, because it is likely that the fatality ratio is far lower. For example, studies of >7,000 healthy individuals have revealed that about 0.5% of them carry antibodies to the virus in their blood, indicating that mild or asymptomatic infections do occur. T-lymphocytes that recognize influenza H5N1 virus have now been detected in a high-risk cohort of individuals in Vietnam, providing additional evidence for asymptomatic human infections.
Viral infection of a healthy host usually leads to the production of both antibodies and lymphocytes. Antibodies generally bind to virus particles in the blood and at mucosal surfaces, blocking the spread of infection. In contrast, T-cells recognize and kill infected cells. The presence of specific antibodies has historically been used as an indicator of viral infection, partly due to the simplicity of the assay. In practice, dilutions of patient sera can be mixed with infectious virus to measure its ability to block infection (virus neutralization or hemaggultination-inhibition), or used to detect antibodies to viral proteins (ELISA or western blot).
Another option for assessing previous viral infection is to determine whether virus-specific T-cells are present. In the past this type of assay has been difficult to carry out with large numbers of samples, but technical advances have now made it possible to do population screens for T-cell responses. In the current study, peripheral blood mononuclear cells (which contain T-lymphocytes and other blood cells) were obtained from patients and placed in culture. Next, pools of overlapping peptides that span most of the influenza viral proteins were added to the cells. These peptides were derived from influenza H5N1, H3N2, and H1N1 proteins. When T-cells recognize a peptide (via the T-cell receptor that recognizes the peptide presented by another cell type; see figure), the cells respond by producing interferon gamma, which can be readily measured.
The Vietnamese patients used for this study were part of a rural community where human and avian infections with influenza H5N1 had been previously documented. Twenty-four of of 747 individuals had evidence for the presence of T-cells that recognize peptides from the H5 HA more strongly than peptides from H3 or H1 HA. Another 111 samples had T-cells that react with H5, H1, and H3 peptides. If all positive patient samples (those lead to production of interferon gamma) are included, then one can conclude that 20% of the patients respond to H5 peptides. Control samples (n=271) were obtained from two individuals in Vietnam and the United Kingdom who are not believed to have been exposed to H5N1 virus. None of these had H5N1-specific T-cell responses.
Curiously, only four subjects had both antibody and T-cell responses to H5N1 virus. The timing of sample acquisition with respect to infection is likely to be important for detecting responses. For example, antibody to H5N1 virus may not be detected earlier than 3 weeks after onset of disease, and T-cell responses may wane with time. It is also possible that abortive H5n1 infections in humans may lead to production of T-cells but not antibodies, as is seen in some individuals infected with HIV-1.
These findings provide additional evidence for subclinical human infection with influenza H5N1 virus. Exactly how many of people in the Vietnamese cohort were infected cannot be determined. Some of the H5-specific responses likely arose from previous H5 infection, while others may represent cross-reactivity with epitopes shared among H1, H3, and H5 viruses. The study also raises the interesting question of whether T-cell assays can be used as diagnostic tests for viral infections.
Powell, T., Fox, A., Peng, Y., Quynh Mai, L., Lien, V., Hang, N., Wang, L., Lee, L., Simmons, C., McMichael, A., Farrar, J., Askonas, B., Duong, T., Thai, P., Thu Yen, N., Rowland-Jones, S., Hien, N., Horby, P., & Dong, T. (2011). Identification of H5N1-Specific T-Cell Responses in a High-risk Cohort in Vietnam Indicates the Existence of Potential Asymptomatic Infections Journal of Infectious Diseases, 205 (1), 20-27 DOI: 10.1093/infdis/jir689
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.
Ichinohe T, Pang IK, Kumamoto Y, Peaper DR, Ho JH, Murray TS, & Iwasaki A (2011). Microbiota regulates immune defense against respiratory tract influenza A virus infection. Proceedings of the National Academy of Sciences of the United States of America, 108 (13), 5354-9 PMID: 21402903
The immune response to viral infection comprises innate and adaptive defenses. The innate response, which we have discussed previously, functions continuously in a normal host without exposure to any virus. Most viral infections are controlled by the innate immune system. However, if viral replication outpaces innate defenses, the adaptive response must be mobilized.
The adaptive defense consists of antibodies and lymphocytes, often called the humoral response and the cell mediated response. The term ‘adaptive’ refers to the differentiation of self from non-self, and the tailoring of the response to the particular foreign invader. The ability to shape the response in a virus-specific manner depends upon communication between the innate and adaptive systems. This communication is carried out by cytokines that bind to cells, and by cell-cell interactions between dendritic cells and lymphocytes in lymph nodes. This interaction is so crucial that the adaptive response cannot occur without an innate immune system.
The cells of the adaptive immune system are lymphocytes – B cells and T cells. B cells, which are derived from the bone marrow, become the cells that produce antibodies. T cells, which mature in the thymus, differentiate into cells that either participate in lymphocyte maturation, or kill virus-infected cells.
Both humoral and cell mediated responses are essential for antiviral defense. The contribution of each varies, depending on the virus and the host. Antibodies generally bind to virus particles in the blood and at mucosal surfaces, thereby blocking the spread of infection. In contrast, T cells recognize and kill infected cells.
A key feature of the adaptive immune system is memory. Repeat infections by the same virus are met immediately with a strong and specific response that usually effectively stops the infection with less reliance on the innate system. When we say we are immune to infection with a virus, we are talking about immune memory. Vaccines protect us against infection because of immune memory. The first adaptive response against a virus – called the primary response – often takes days to mature. In contrast, a memory response develops within hours of infection. Memory is maintained by a subset of B and T lymphocytes called memory cells which survive for years in the body. Memory cells remain ready to respond rapidly and efficiently to a subsequent encounter with a pathogen. This so-called secondary response is often stronger than the primary response to infection. Consequently, childhood infections protect adults, and immunity conferred by vaccination can last for years.
The nature of the adaptive immune response can clearly determine whether a virus infection is cleared or causes damage to the host. However, an uncontrolled or inappropriate adaptive response can also be damaging. A complete understanding of how viruses cause cause disease requires an appreciation of the adaptive immune response, a subject we’ll take on over the coming weeks.