Once again, respiratory viruses are your friends

As humans we have the tendency to want to control things that we don’t understand. Most of the time, this ends badly. We act based on the information we have, rather than not acting, based on our realization that we don’t have all information. And when it comes to something as complex as our relationship to the respiratory viruses that are part of the human holobiont, that has me worried.

As an example, I would ask you to look at the flu shot. Countries that now constantly vaccinate their elderly against influenza haven’t seen a substantial decline in influenza deaths. So why do we do it? Because of the economic incentives of capitalism: Products the government subsidizes are very profitable. Products that require specialized knowledge to produce are very profitable. Products that have to be updated every year are also very profitable. Products marketed at affluent elderly are also very profitable. Influenza checks all these boxes, so there will be massive forces in society pushing for vaccination against influenza. If you were to argue it’s counterproductive to vaccinate against influenza, you’re up against massive entrenched interest groups.

I’m not just interested in the question of whether these influenza vaccines genuinely prevent influenza infection. When you ask yourself this question, you’ve already made concessions without realizing it. I’m starting at the absolute top of the chain of decision making process, by asking a question all of you take for granted: Is influenza a villain?

When we take it for granted that influenza is a villain, that doesn’t necessarily mean eliminating influenza is a good thing. Removing a villain known as Saddam Hussein did not make Iraq a more stable and peaceful place. What fills the vacuum, when we remove influenza? You have no proper answer to this question.

But let us move back to step one: We have to establish that influenza is a villain. It’s not enough to say that influenza kills people. Influenza kills 12-52.000 Americans every year. Medical errors on the other hand, kill 215.000 people in the US every year. We don’t give everyone vaccines against doctors. We don’t seek to eradicate nurses off the face of the planet. We realize they try to fill a niche to the best of their ability, sometimes unfortunately killing people in the process.

Now ask yourself: What about influenza? Is influenza attempting to fulfill a niche? I would argue it is. In a given year, 140,000 Americans die of lung cancer. Whenever influenza infects the lungs, it trains the immune system in the lung microenvironment. The cells that are tasked with eliminating cancer are largely the same sort of cells tasked with eliminating influenza: CD8+ T cells, Natural Killer cells, macrophages and so forth.

Now have a look at what happens in mice, when they are exposed to influenza:

Respiratory viral infections reprogram pulmonary macrophages with altered anti-infectious functions. However, the potential function of virus-trained macrophages in antitumor immunity in the lung, a preferential target of both primary and metastatic malignancies, is not well understood. Using mouse models of influenza and lung metastatic tumors, we show here that influenza trains respiratory mucosal-resident alveolar macrophages (AMs) to exert long-lasting and tissue-specific antitumor immunity. Trained AMs infiltrate tumor lesions and have enhanced phagocytic and tumor cell cytotoxic functions, which are associated with epigenetic, transcriptional and metabolic resistance to tumor-induced immune suppression. Generation of antitumor trained immunity in AMs is dependent on interferon-γ and natural killer cells. Notably, human AMs with trained immunity traits in non-small cell lung cancer tissue are associated with a favorable immune microenvironment. These data reveal a function for trained resident macrophages in pulmonary mucosal antitumor immune surveillance. Induction of trained immunity in tissue-resident macrophages might thereby be a potential antitumor strategy.

And have a good look at what happened to these mice that already had lung cancer, upon exposure to a mild influenza strain:

Non-small-cell lung cancer (NSCLC) is the most frequent type of lung cancer and demonstrates high resistance to radiation and chemotherapy. These tumors evade immune system detection by promoting an immunosuppressive tumor microenvironment. Genetic analysis has revealed oncogenic activation of the Ras/Raf/MEK/ERK signaling pathway to be a hallmark of NSCLCs, which promotes influenza A virus (IAV) infection and replication in these cells. Thus, we aimed to unravel the oncolytic properties of IAV infection against NSCLCs in an immunocompetent model in vivo. Using Raf-BxB transgenic mice that spontaneously develop NSCLCs, we demonstrated that infection with low-pathogenic IAV leads to rapid and efficient oncolysis, eliminating 70% of the initial tumor mass. Interestingly, IAV infection of Raf-BxB mice caused a functional reversion of immunosuppressed tumor-associated lung macrophages into a M1-like pro-inflammatory active phenotype that additionally supported virus-induced oncolysis of cancer cells. Altogether, our data demonstrate for the first time in an immunocompetent in vivo model that oncolytic IAV infection is capable of restoring and redirecting immune cell functions within the tumor microenvironment of NSCLCs.

Interestingly enough, the same thing is observed for SARS2.

Alright you say, but this is just in mice. Well, have a look at this, in lung cancer patients:

To determine whether our findings have corresponding clinical relevance, we surveyed the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database of over 30,000 patients with lung cancer. We found that patients who had 1 or more hospitalizations for influenza virus infection during their lung cancer course exhibited decreased lung cancer-specific and overall mortality (Fig. 1 D and E), in agreement with our mouse model observations. Importantly, the time to lung cancer-specific mortality and overall mortality in 25% of each population was prolonged 12 and 19 mo, respectively, for patients with 1 or more hospitalizations for influenza virus infection during their lung cancer course (Fig. 1 F and G).

Lung cancer patients tend to be terrified of catching influenza. And yet, the evidence we have suggests they would be better off if they did.

So is it just lung cancer we’re talking about? Well, if we take what we know from the above studies, I expect you may prevent COPD through the occasional influenza infection too. Have a look at this:

Alveolar macrophages in early stage COPD show functional deviations with properties of impaired immune activation

Despite its high prevalence, the cellular and molecular mechanisms of chronic obstructive pulmonary disease (COPD) are far from being understood. Here, we determine disease-related changes in cellular and molecular compositions within the alveolar space and peripheral blood of a cohort of COPD patients and controls. Myeloid cells were the largest cellular compartment in the alveolar space with invading monocytes and proliferating macrophages elevated in COPD. Modeling cell-to-cell communication, signaling pathway usage, and transcription factor binding predicts TGF-β1 to be a major upstream regulator of transcriptional changes in alveolar macrophages of COPD patients. Functionally, macrophages in COPD showed reduced antigen presentation capacity, accumulation of cholesteryl ester, reduced cellular chemotaxis, and mitochondrial dysfunction, reminiscent of impaired immune activation.


COPD alveolar macrophages differ from healthy controls, releasing lower levels of pro-inflammatory cytokines in response to Lipopolysaccharide (LPS) stimulation1718, and showing suppression of M1 related genes19. COPD alveolar macrophages also have a reduced ability to efferocytose apoptotic epithelial cells20 and phagocytose bacteria21

I hope that this attempt to turn respiratory viruses into a thing of the past remains nothing more than a pipe dream among academics on Twitter.


  1. A symbiotic relationship between homosapiens and influenza is at the very least an interesting concept. A ‘selfish gene’ evolutionary perspective would suggest that the flu would like to keep people around so they could continue to infect them in the future.

    • Part of the question lies in how we wish to define symbiotic. Imagine my ethnic group carries a pathogen we’ve developed resistance against over time, so that it hardly kills anyone.

      Now imagine a neighboring tribe invades my region. Upon contact they catch this pathogen and begin to die in droves. Is the pathogen symbiotic to my ethnic group?

      Now replace ethnic group with species. A lion walks into a cave, begins eating bats and dies of ebola. Is ebola symbiotic to the bats?

  2. It’s not even necessarily symbiosis, if something external to the body causes a process in the body that helps it, the body will never evolve its own way of doing that process. We are not symbiotic with the sun and yet the sun causes processes in our own bodies that presumably, the body could evolve to do without.

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