The susceptibility and recovery from various pulmonary infections have been observed to have a sex bias, depending on the microbial pathogen. For instance, researchers have known that women, compared to men, tend to have more severe flu with slower recoveries even when their virus levels are the same. It had been thought that this was due solely to women's greater levels of lung inflammation during flu infections. However, now investigators at Johns Hopkins Bloomberg School of Public Health have new evidence showing that men produce more of a key lung-healing protein, allowing them to recover more quickly from influenza infections.      

Findings from the new study—published recently in Biology of Sex Differences through an article titled “Production of amphiregulin and recovery from influenza is greater in males than females”—could lead to new flu treatments that boost the lung-healing protein production, particularly in women.

In the current study, the Hopkins team infected live mice and human cells derived from male humans with influenza virus and found that both the male mice and human cells produced more amphiregulin (AREG), a growth factor protein important in wound healing. The male mice recovered more quickly, compared to female mice, whereas male mice lacking amphiregulin had recovery times close to those of females.

“The novel finding here is that females also have slower tissue-repair during recovery, due to the relatively low production of amphiregulin,” explained senior study investigator Sabra Klein, Ph.D., an associate professor in the department of molecular microbiology and immunology at the Bloomberg School.

Dr. Klein and her colleagues administered a non-lethal dose of H1N1, an Influenza A strain that caused a global pandemic in 2009-10 with more than 18,000 deaths. The researchers observed that although male and female mice had similar levels of virus and cleared it in about the same amount of time, the females suffered significantly more from their infections. They had greater loss of body mass and greater lung inflammation during the acute phase of infection, and later they were slower to recover normal lung function.

Consequently, the scientists identified AREG as a key factor in this gender-based difference. This growth-factor protein is known to promote the proliferation of epithelial cells in the skin, lung, and other surfaces in the body during wound healing, including recovery from lung infections. Analysis of the mice revealed that males produced significantly more AREG than females during the recovery phase of their infections.

“As compared with females, AREG expression was greater in the lungs of male mice as well as in primary respiratory epithelial cells derived from mouse and human male donors, in response to H1N1 IAVs,” the authors wrote. “Internalization of the epidermal growth factor receptor (EGFR) was also greater in respiratory epithelial cells derived from male than female mice. IAV infection of Areg knock-out (Areg−/−) mice eliminated sex differences in IAV pathogenesis, with a more significant role for AREG in infection of male compared to female mice. Deletion of Areg had no effect on virus replication kinetics in either sex. Gonadectomy and treatment of either wild-type or Areg−/− males with testosterone improved the outcome of IAV as compared with their placebo-treated conspecifics.”

Additionally, the research team found that flu infections of mouse and human lung epithelial cells in culture dishes were followed by significant jumps in the production of amphiregulin only when the cells were from males.

The fact that amphiregulin helps ameliorate flu infection points to a new therapeutic strategy for severe flu. Previously, Dr. Klein and her colleagues showed that the sex hormone progesterone stimulates amphiregulin production in female mice. “We found in that study that by increasing amphiregulin production in females we could expedite their recovery from flu,” Dr. Klein notes.

However, researchers have not yet determined why males are more resistant to flu effects. Greater wound-healing ability may have conferred a reproductive advantage for males—who, from an evolutionary standpoint, has probably been more frequently wounded on average, in battles for territories, mates, and resources. That advantage may not have been as strong in females, Dr. Klein suggests.

It isn't yet clear which factors drive the greater rise in amphiregulin production in males during flu infection. The research team suspected this was attributable to testosterone at first but found it does not seem to control amphiregulin levels. Though, they found that the sex hormone, independently of amphiregulin, does help protect male mice, who fared worse in flu infections without it.

Dr. Klein's laboratory is now investigating the mechanisms of testosterone's protective effect, as well as the upstream factors that control amphiregulin production during flu infection.

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