When Viruses Invade, the Mighty Macrophage Packs a Punch
There are two sides to macrophages. On a good day, they are mighty defenders that work as part of the innate immune system to sound the alarm and clear pathogens. But if they get too excited, they can leave the body in shambles. Could controlling this duality of macrophage behavior be the key to reducing mortality from infectious diseases, like COVID-19?
This article is posted on our Science Snippets Blog
Giant Pathogen Gobblers
Macrophages have always been a favorite of immunologists. Under the microscope, they appear as big cellular garbage trucks that gobble up pathogens, and clear erythrocytes and cellular debris. They act as part of our innate immune system, which provides the first line of defense against foreign invaders.
When respiratory viruses enter the lung, the innate immune response is initiated. Alveolar macrophages are one of the first to arrive at the scene and get to work: 1) they phagocytose intruders and present their antigens, 2) they secrete cytokines and chemokines to initiate inflammation and leukocyte recruitment, 3) they produce antiviral proteins, such as interferons, to stop viral replication.
In the best-case scenario, the infection is overcome by a finely tuned immune response that destroys and eliminates the pathogen. This balance is achieved by an anti-inflammatory counter measure involving a different subset of macrophages that turn off the body’s response as the infection subsides. However, the ability to keep things in check can sometimes go awry.
Immune System in Overdrive
Some people develop severe pneumonia following bacterial and viral infections, as we have seen in hospitalized COVID-19 patients. This happens when the proinflammatory immune response goes out of control and causes a condition called acute respiratory distress syndrome (ARDS). In these patients, inflammatory cytokines and chemokines are overproduced, resulting in tissue damage and fluid accumulation in the lungs. In the sickest of patients, ARDS leads to organ failure and death.
Controlling this collateral damage is one way researchers are trying to prevent ARDS following infection with respiratory pathogens.
Dr. Daniel Goldstein’s lab at the University of Michigan is approaching this question by studying the role of macrophage migration inhibitory factor (MIF). MIF is a cytokine protein that can regulate the innate immune response in various ways, for example by blocking apoptosis, activating macrophages, and stimulating the NLR family pyrin domain containing (3NLRP3) inflammasome.
In a recent publication from his lab, lead scientist Dr. Candice Smith and colleagues investigated the role of MIF in macrophage regulation in a mouse model of influenza (strain PR8). (Read study: Smith CA et al. Macrophage migration inhibitory factor enhances influenza-associated mortality in mice. JCI Insight. 2019 Jul 11;4(13). )
Using a combination of mice studies and live cell culture assays on the Incucyte® System they found that MIF impairs the anti-viral immunity of the host, causing more inflammation during influenza infection. We talked with Dr. Goldstein about their findings and how it could inform new anti-viral therapeutics.
Pharmacological Analysis of Apoptosis in High Throughput. This figure shows how the Incucyte® Live-Cell Analysis System and live-cell apoptosis assays can be used to monitor apoptosis in real time, similar to the assay used in the MIF study. A549 cells were seeded (2,000 cells/well) and after 18 h treated with vehicle control and camptothecin in the presence of Incucyte® Annexin V NIR. Phase and NIR (pseudo-colored blue) fluorescent images (20X; 72 h) show apoptotic readouts correlated with morphological changes.
Interview with Dr. Daniel Goldstein: MIF and Infection
Sartorius: What key findings led you to this important discovery about MIF?
Dr. Goldstein: My collaborator Dr. Richard Bucala (Rick) who was a colleague of mine at Yale School of Medicine, is the leading authority on MIF. His laboratory has found that MIF plays roles in many diseases including rheumatological, vascular and host defense. Yet the role of MIF was strangely undefined. This was a gap in knowledge that needed to be filled. Rick inspired me to examine this.
Sartorius: How did you use live-cell analysis to investigate the role of MIF in inflammation during infection by influenza?
Dr. Goldstein: We used fluorescently-tagged influenza virus to investigate how MIF controlled viral infection. We found that MIF promoted viral spread.
Sartorius: Could differences in basal gene expression of MIF play a role in the severity of illness that we see with viral infections, such as COVID-19? How might MIF levels be altered in response to age and pre-existing conditions?
Dr. Goldstein: Yes, this is a great point. Rick has found that the 5′ promoter of the MIF gene contains a microsatellite repeat (CATT)5–8 that regulates transcription, and that high MIF levels are detrimental for some viral infections, like West Nile infection. MIF could be regulated by aging and potentially act as a marker of risk for viral infection. How MIF is involved in COVID-19 is unknown, but potentially very relevant.
Sartorius: How might targeting MIF aid in reducing the mortality of high-risk individuals?
Dr. Goldstein: It is possible that MIF acts as a “bad player” during a respiratory viral infection. Blocking it or the pathway it acts upon could increase viral control, reduce inflammation and increase survival in susceptible populations.
Among our arsenal of immune fighters, the macrophage can be either friend or foe. Understanding how macrophage function is regulated can lead to new therapeutic targets for preventing ARDS following infection. Live-cell analysis is a powerful technique for visualizing immune cell function in real-time, without removing cells from the tissue culture hood.
