Summary of:
Robinson, D.P., Hall, O.J., Nilles, T.L., Bream, J.H., and Klein, S.L. (2014). 17β-estradiol Protects Females against Influenza by Recruiting Neutrophils and Increasing Virus-Specific CD8 T Cell Responses in the Lungs. Journal of Virology. Vol. 88:9 p. 4711-4720. http://jvi.asm.org/content/88/9/4711.long
Influenza viruses cause contagious respiratory illness with a sudden onset of high fever, cough, sore throat, runny or stuffy nose, body aches, headache, and fatigue. There are 3 types of influenza viruses (A, B, and C) with influenza A and B viruses causing seasonal epidemics of disease. The Centers for Disease Control (CDC) estimates that flu-associated deaths range from 3000-49,000 each year depending on length and severity of the season (see the CDC website for more general information about the flu virus, http://www.cdc.gov/flu/about/disease/us_flu-related_deaths.htm). Moreover, pulmonary inflammatory diseases such as influenza are known to differentially affect males and females with women suffering a worse outcome. Prior evidence indicates that estrogen impacts the function of various immune cells and therefore may contribute to the differential outcomes between men and women following respiratory infections. The authors of this paper aimed to examine the role of estradiol (E2, one of the 2 major biologically active estrogens in non-pregnant humans) in both the host response to the influenza A virus (IAV) and the ability of IAV to replicate in the host. It was hypothesized that estradiol alters the recruitment and activity of immune cells therefore affecting the outcome of IAV infection. In order to test this hypothesis, female C57BL/6 mice were ovariectomized and implanted with either E2 or placebo capsules followed by infection with IAV. E2 treatment resulted in less morbidity as compared to placebo-treated females. E2 did not affect virus replication, but increased the levels of chemokines in lung homogenates, increased recruitment of neutrophils to the lungs, and increased the levels of interferon-γ and tumor necrosis factor-α released from virus-specific CD8 T cells. These effects were dependent on neutrophils because depletion of neutrophils in females treated with E2 increased morbidity, reduced chemokine production, and reduced CD8 T cell IFN-g production. In summary, sustained E2 levels affect the host response to IAV infection through a neutrophil-dependent mechanism leading to improved outcomes. This work sets the stage for further mechanistic studies related to how E2 regulates these effects and supports the consideration of E2 levels in the treatment of IAV infected patients.
The paper introduces the topic with a description of estradiol as a pro-inflammatory hormone. However, their experiments lead them to conclude that E2 treatment has strong anti-inflammatory effects in the case of IAV. I did not see where they addressed this discrepancy, and I am curious how we can resolve these seemingly opposite effects into a more specific understanding of the actions of estradiol. Is it the body’s recognition of an excess of an endogenous molecule that initiates mechanisms to temper its reaction to the viral infection?
Overall, I am fascinated by the finding in this paper that the female mice treated with estradiol experienced less morbidity as compared to the placebo-treated mice. Specifically, I find the possible explanations for this quite interesting, especially the idea of “disease tolerance”. The females treated with E2 had a lower fitness cost than the placebo-treated females. However I am slightly confused by how this implies that females are therefore not protected from the disease due to resistance, but are instead more tolerant to the fitness costs that come with infection.
This article brought up an interesting fact in saying that women are more susceptible to and suffer a worse outcome when dealing with inflammatory-mediated pulmonary diseases. This was a fact that never occurred to me and I understand why the effect of the E2 estrogen hormone is being studied. After reading the article, I believe that it would be interesting to further study the “disease tolerance” theory. The paper concludes that E2 protects females, not by making them more resistant to infection but by making them more tolerant to the costs associated with infection. I feel that the mechanics of this process should be further examined and studying other possible hormones that promote “disease tolerance” would shed some light on the topic.
In the discussion, the authors mention that neutrophils contain both ER-alpha and ER-beta receptors. Is there an advantage resulting from possession of both ER-alpha and ER-beta?
In the last paragraph of this paper, Robinson et. al (2014) review the idea that if E2 treatment were to increase resistance against IAV, then EF-treated females would have lower virus titers than placebo-treated females. However, their data demonstrate that the kinetics of IAV replication in the lungs of E2-treated and placebo-treated females were very similar. Depletion of neutrophils post-IAV infection also had no affect on the ability of E2-treated females to control virus replication, so they concluded that E2 must instead regulate damage caused by the infection. This makes me wonder what (hormones, etc.) could function to eliminate IAV from the lungs, which is something I do not think they elude to in this paper. Would this discovery as well as E2 treatment be the most effective method for treating IAV?
balance between virus clearance and inflammatory disease during IAV infection. In particular, the role of sustained levels of estradiol has a significant effect on IAV infection and reduced morbidity. In the paper, they conclude that estradiol (E2) protects females from severe influenza by limiting the negative impact of infection of host fitness. I am more curious about how they concluded this from their data. In particular, what is their explanation for how females are protected from IAV infection by being more tolerant to the costs that come with the infection instead of becoming more resistant to the disease?
I thought the findings of this article concerning E2’s effect of increasing disease tolerance were interesting. It makes me wonder if there are hormones in males that have a similar effect. Is it also possible that males have a small amount of this hormone as well or are there other hormones with similar effects?
The data given in this paper does provide evidence showing that during IAV infection, E2’s protective effects are neutrophil dependent. Because there was no observed decrease in viral titers, this treatment was described as a hormone that could potentially limit the damage of the infection. Thinking about this “disease tolerance” perspective of the treatment with this hormone, I wonder what the administration of E2 would look like for women during times of infection. It this something that should be done proactively, or could hormone administration be more effectively used after diagnosis of infection to reduce the time of symptoms surrounding IAV infection?
As touched on in class and stated in the paper, estradiol has contrasting effects depending on concentrations, and I am curious how the same hormone could have the ability to both cause an enhancement in proinflammatory cytokines as well as reduce their production. Also, to me, this raises the questions of 1) Does the low level of E2 in males have any effect to their survival and quality of health during and IAV infection and 2) if low levels of E2 result in enhancing proinflammatory cytokine responses, why are males still at lower risk for severe infection compared to females?
It was interesting to see another paper on the effects of estradiol on the immune and inflammatory responses following the experiment in physiology last semester. This approach allowed for more specific control of the hormone, and therefore the ability to have more reliable results. In figure 5, I would want to look more into the different levels of t-cells between the lungs and lymph nodes, in E2 mice the t-cells increased in the lungs, but there was no effective change in the lymph nodes. This finding was interesting to me because I would have thought the lymphatic system would have had a similar change since it is active throughout the body and would seem to have input or signals when the lungs had an immune response to the IAV.
One issue that I had with this article that I don’t believe the authors addressed is that in figure three, the number of neutrophils is not greater in the lungs of E2 (+) mice until seven days post infection. In fact, at five days post infection there are more neutrophils in E2 (-) mice. From this data the authors conclude that neutrophil recruitment is “E2 dependent,” but I am not sure this is clear from the data. It may be that the time frame of recruitment is just shifted. Why does it take a whole week for this effect to become visible? Does the Influenza incubation period account for the delay?
I am also interested about the method the authors used to measure viral titre. They say that they measured cytopathic effects on cells, but I am curious what those effects were.
This article was incredibly thought-provoking for its implications of a correlation between sex hormones and IAV. I would be interested to see if future, subsequent studies might look at E3 as I would think the findings of estrogen levels during pregnancy would further enhance the findings of this study. From an evolutionary standpoint, it would seem likely that the immune system would be stronger and working harder to fight off IAV when attempting to host a new life. It would be interesting to see if high E3 levels would be correlated with a decrease in IAV infection as immunity to IAV would seem much more critical during pregnancy. It would seem reasonable that high levels of E3 would help decrease the chances of IAV infection at a time when the immune system is working harder to keep both the pregnant woman and baby healthy.
It was interesting that they defined what “disease tolerance” means by referring to their experiment. By clarifying that word, it actually makes sense that estrogen could possibly protect from infection, IAV. It was also interesting that E2-treated inflammatory responses (CCL2) had decreased level and it was not different with anti-inflammatory cytokines levels. I was confused why the anti-inflammatory cytokines produced the same effect with E2-treated and placebo-treated females. And also, since the data were not shown, I was confused whether anti-inflammatory cytokines produced the same effect only with E2-treated or only with placebo-treated females. It would be much interesting if they investigated on how E1 or E3 affect or not affect IAV, as well. Furthermore, it would be also interesting if they explore on how progesterone or testosterone can affect IAV. For figure 5, It was interesting that they concluded E2 sometimes increases the proportion of virus-specific T cells. However, I was wondering what would be the reason why E2 is selectively producing increased TNF-alpha or the other cytokine. And what would be the reason why E2 does not quantitatively increase the number of cytokines in response to influenza virus antigen (Figure 5). Overall, it was interesting for me to know neutrophil could affect the E2 for protecting from IAV because I studied on how human neutrophils could over the immune system through a PhoPQ TCS, type III secretion system, and efferocytosis.
I understand that the E2 supplemented mice had a relative decreased morbidity in response to influenza A virus (IAV) infection that was dependent on neutrophils. What I cannot seem to wrap my head around is why there is not a neutrophil dependent/mechanistic response to infection with IAV in those without E2. Does this mean that the presence of neutrophils is only going to be effective in decreasing morbidity in the presence of E2. How can this mechanism of decreasing morbidity be isolated to the effects of neutrophils if it is only the case with those mice that have been given E2.
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