Estrogen and other sex hormones put women at greater risk than men in their responses to some viral infections and vaccines, according to several participants who spoke during the symposium “Men, Women, Infection, and Infertility,” convened as part of the 2013 ASM General Meeting last May in Denver.
While heightened immune responses make women typically less susceptible than men tomany bacterial and viral infections, those heightened immune responses sometimes prove damaging.
For example, once infected by HIV and despite their viral loads remaining relatively lower, women tend to progress to AIDS faster than do men, says Marcus Altfeld of the Ragon Institute of Massachusetts General Hospital in Boston, Mass. This difference is due, in part, to how the hormones estrogen and progesterone affect innate immune responses. These two hormones, which circulate in women but not in men, induce higher levels of the Tolllike receptor (TLR) 7 as well as a specifıc signal transducer molecule that contributes toTLR7 activation, he says. TLR7 detects single-stranded viral RNA and initiates immune responses to such viruses.
“Plasma dendritic cells derived from women produce twice as much interferon γ (IFN-γ) in response to TLR7, resulting in stronger secondary activation of CD8+ T cells,” Altfeld continues. Ultimately, increased IFN-γ production in females drives cytotoxic T cells to destroy CD4 cells, enabling the disease to progress more rapidly. Thus, he suggests targeting TLR7 in women to slow HIV and possibly other RNA viruses with similar gender-specifıc effects. Such antagonists are in development for treating autoimmune disorders such as lupus, which are TLR7 dependent and overrepresented in women.
Women are also more susceptible than men to influenza, according to Sabra Klein of Johns Hopkins Bloomberg School of Public Health in Baltimore. Estrogen accentuates inflammatory responses and promotes immunopathology, she says. “Titers of infectious virus in the lungs do not differ between the sexes . . . (but) females show greater induction of cytokines and chemokines, including chemokine ligand (CCL)-2, tumor necrosis factor α (TNF-α), IFN-γ, and interleukin 6.” Influenza induces inflammation in females by disrupting the estrous cycle when estrogen is at its low. At low concentrations estrogen promotes inflammation, whereas at higher concentrations estrogen suppresses inflammation and promotes the T-helper (Th) 2 response. Moreover, in experiments with mice, treating influenza-infected females with estrogen protects them against morbidity and mortality by suppressing inflammatory responses, Klein and her collaborators fınd.
Together these fındings suggest that gender should be taken into account when designing vaccines, according to Klein. Some vaccines act through TLR7, including the yellow fever vaccine. “Antibody responses to bacterial and viral vaccines are consistently at least twice as high in women,” she says. Moreover, she adds, a heightened immune response, and unnecessarily high dosing, may help to explain why women report more frequent and severe adverse reactions to vaccines than do men. This difference might explain why a vaccine to protect against the herpes simplex virus failed to show protection after phase 2 clinical trials. “When data were analyzed by sex, the effıcacy of the vaccine was 73% in women and only 11% in men,” she says.
Shannon Weiman is a freelance writer in San Francisco, Calif.