By Jacob L. Steenwyk and Antonis Rokas
From the mythical minotaur to the mule, creatures created from merging two or more distinct organisms – hybrids – have played defining roles in human history and culture. However, not all hybrids are as fantastic as the minotaur or as dependable as the mule; in fact, some of them cause human diseases.
When Looking Through a Microscope Isn’t Close Enough.<p>For the last few years, <a href="http://www.rokaslab.org/" target="_blank">our team at Vanderbilt University</a>, <a href="https://www.researchgate.net/lab/Gustavo-Goldman-Lab" target="_blank">Gustavo Goldman's team at São Paulo University in Brazil</a> and many other collaborators around the world have been collecting samples of fungi from patients infected with different species of <em>Aspergillus</em> molds. One of the species we are particularly interested in is <a href="https://doi.org/10.1006/rwgn.2001.0082" target="_blank"><em>Aspergillus nidulans</em>, a relatively common and generally harmless fungus</a>. Clinical laboratories typically identify the species of <em>Aspergillus</em> causing the infection by examining cultures of the fungi under the microscope. The problem with this approach is that very closely related species of <em>Aspergillus</em> tend to look very similar in their broad morphology or physical appearance when viewing them through a microscope.</p><p>Interested in examining the varying abilities of different <em>A. nidulans</em> strains to cause disease, we decided to analyze their total genetic content, or genomes. What we saw came as a total surprise. We had not collected <em>A. nidulans</em> but <em>Aspergillus latus</em>, a close relative of <em>A. nidulans</em> and, as we were to soon find out, <a href="https://doi.org/10.1016/j.cub.2020.04.071" target="_blank">a hybrid species that evolved through the fusion of the genomes</a> of two other <em>Aspergillus</em> species: <em>Aspergillus spinulosporus</em> and an unknown close relative of <em>Aspergillus quadrilineatus</em>. Thus, we realized not only that these patients harbored infections from an entirely different species than we thought they were, but also that this species was the first ever <em>Aspergillus</em> hybrid known to cause human infections.</p>
Several Different Fungal Hybrids Cause Human Disease.<p>Hybrid fungi that can cause infections in humans are well known to occur in several different lineages of single-celled fungi known as yeasts. Notable examples include multiple different species of <a href="https://doi.org/10.1002/yea.3242" target="_blank">yeast hybrids</a> that cause the human diseases <a href="https://rarediseases.info.nih.gov/diseases/6218/cryptococcosis" target="_blank">cryptococcosis</a> and <a href="https://www.cdc.gov/fungal/diseases/candidiasis/index.html" target="_blank">candidiasis</a>. Although pathogenic yeast hybrids are well known, our discovery that the <em>A. latus</em> pathogen is a hybrid is a first for molds that cause disease in humans.</p>
(Left) Candida yeasts live on parts of the human body. Imbalance of microbes on the body can allow these yeasts, some of which are hybrids, to grow and cause infection. (Right) Cryptococcus yeasts, including ones that are hybrids, can cause life-threatening infections in primarily immunocompromised people. Centers for Disease Control and Prevention<p><a href="https://doi.org/10.1371/journal.ppat.1008315" target="_blank">Why certain <em>Aspergillus</em> species are so deadly</a> while others are harmless remains unknown. This may in part be because <a href="https://doi.org/10.1016/j.fbr.2007.02.007" target="_blank">combinations of traits, rather than individual traits</a>, underlie organisms' ability to cause disease. So why then are hybrids frequently associated with human disease? Hybrids inherit genetic material from both parents, which may result in new combinations of traits. This may make them more similar to one parent in some of their characteristics, reflect both parents in others or may differ from both in the rest. It is precisely this mix and match of traits that hybrids have inherited from their parental species that <a href="https://www.nytimes.com/2010/09/14/science/14creatures.html" target="_blank">facilitates their evolutionary success</a>, including their ability to cause disease.</p>
The Evolutionary Origin of an Aspergillus Hybrid.<p>Multiple evolutionary paths can lead to the emergence of hybrids. One path is through mating, just as the horse and donkey mate to create a mule. Another path is through the merging or fusion of genetic material from cells of different species.</p><p>It is this second path that appears to have been taken by our fungus. <em>A. latus</em> appears to have two of almost everything compared to its parental species: twice the genome size, twice the total number of genes and so on. But unlike other hybrids, which are often sterile like the mule, we found that <em>A. latus</em> is capable of reproducing both asexually and sexually.</p><p>But how distinct were the parents of <em>A. latus</em>? By comparing the parts contributed by each parent in the <em>A. latus</em> genome, we estimate that its parents are approximately 93% genetically similar, which is about as related as we humans are with lemurs. In other words, <em>A. latus</em>, an agent of infectious disease, is the fungal equivalent of a human-lemur hybrid.</p>
How A. Latus Differs From its Parents.<p>Elucidating the identity of closely related fungal pathogens and how they differ from each other in infection-relevant characteristics is a key step toward reducing the burden of fungal disease. For example, we found that <em>A. latus</em> was three times more resistant than <em>A. nidulans</em>, the species it was originally identified as using microscopy-based methods, to one of the most common antifungal drugs, <a href="https://www.drugbank.ca/drugs/DB00520" target="_blank">caspofungin</a>. This result provides a clear example of the potential importance of accurate identification of the <em>Aspergillus</em> pathogen causing an infection.</p><p>We also examined how <em>A. latus</em> and <em>A. nidulans</em> interact with cells from our immune system. We found that immune cells were less efficient at combating <em>A. latus</em> compared to <em>A. nidulans</em>, suggesting the hybrid fungus may be trickier for our immune systems to identify and destroy.</p><p>In the midst of the COVID-19 pandemic, our quest to understand <em>Aspergillus</em> pathogens is becoming more urgent. Growing evidence suggests that <a href="https://doi.org/10.1111/myc.13096" target="_blank">a fraction of COVID-19 patients are also infected with <em>Aspergillus</em>.</a> More worrying is that these <a href="https://doi.org/10.3201/eid2607.201603" target="_blank">secondary <em>Aspergillus</em> infections</a> can worsen the clinical outcomes for those infected with the novel coronavirus. That being said, we stress that little is known about <em>Aspergillus</em> infections in COVID-19 patients due to a lack of systematic testing, and none of the infections identified so far appear to have been caused by hybrids.</p><p>So, when it comes to hybrids, some are fantastic (the minotaur), some are helpful (the mule) and some are dangerous (<em>Aspergillus latus</em>). Understanding more about the biology of <em>Aspergillus latus</em> may help in our understanding of how microbial pathogens arise and how to best prevent and combat their infections.</p>
Scuba divers around the world are holding their metaphorical breath to see if a coronavirus infection affects the ability to dive.
DAN medical experts explained the difference between normal lungs, on the left, and "very serious lungs caused by COVID-19," on the right. Matias Nochetto / Divers Alert Network (DAN)
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By Cathy Cassata
With more than 1.7 million confirmed cases of COVID-19 in the United States and more than 100,000 deaths from the virus, physicians face unprecedented challenges in their efforts to keep Americans safe.
They also encounter what some call an "infodemic," an outbreak of misinformation that's making it more difficult to treat patients.
When Leaders and Doctors Spread Misinformation<p>When people in charge of towns, cities, states, and countries spread misinformation, the potential for belief in misinformation to result in policies can have harmful effects.</p><p><a href="https://www.northwell.edu/find-care/find-a-doctor?q=Bruce+E.+Hirsch%2C+MD&insurance=&location=&query_type=provider&physician_partners=false&default_view=list&gender=&language=&sort=relevancy" target="_blank">Dr. Bruce E. Hirsch</a>, attending physician and assistant professor in the infectious disease division of Northwell Health in Manhasset, New York, says an example of this is when President Trump informed the public he was taking hydroxychloroquine as a preventive measure.</p><p>"To approach this enormous challenge, we need some intellectual honesty and clarity, and to disregard expertise and to make decisions and model decisions based on hunches is inviting us to handle challenges on the basis of rumor and uninformed opinion. The magnitude of that error is epic," Hirsch told Healthline.</p><p>Stukus agrees, noting that the harm of this proclamation is documented.</p><p>"Early on when the president touted the benefits of hydroxychloroquine and azithromycin, people started to hoard this medicine, and state boards had to shut it down because they were getting so many prescriptions for this unproven therapy that it was not available for those who truly needed it, such as those who have lupus and autoimmune conditions," Stukus said.</p><p>He adds that calls to poison control centers increased after the president suggested using disinfectant to prevent contracting the new coronavirus.</p>
Listen to Science, Even When it Changes<p>When recommendations change or evidence flip-flops, skepticism may arise. However, Stukus says change is the beauty of science.</p><p>"That shows us that we can evolve, and if the evidence shows that our prior thoughts were incorrect, we need to be able to change our recommendations and advice based upon the best quality of evidence at the time," he said.</p><p>Pierre agrees.</p><p>"Science is an iterative process, whereby we arrive at facts and truth through repeated and controlled observations. That means that it's inherently self-correcting as we revise conclusions based on ongoing research. Scientific facts aren't immutable dogma chiseled on a tablet. They change based on the best available evidence we have at a given point in time," he said.</p><p>Because research of COVID-19 has only been underway for 6 months, information is evolving rapidly, and new information may contradict old.</p><p>"There's still much we don't know about exactly how [COVID-19] spreads, what effects it has on the body, or how to best treat it. That means that the best available evidence is preliminary, but that doesn't mean that we should ignore it or turn to other sources of information or opinion as if they're just as valid," Pierre said.</p><p>He explains that conspiracy theories based on mistrust lead to vulnerability to misinformation.</p><p>If people mistrust science because it sometimes "changes its mind," Pierre said, "that shouldn't be used to embrace other opinions based on no evidence at all, which are typically selected based on confirmation bias: what we want to believe rather than what the objective evidence supports."</p>
Where to Find the Best Information<p>Stukus says to start with the <a href="https://www.cdc.gov/coronavirus/2019-nCoV/index.html" target="_blank">CDC</a> and <a href="https://www.nih.gov/health-information/coronavirus" target="_blank">NIH</a>. Then check with your local health officials, because COVID-19 guidelines may vary depending on where you live.</p><p>If you can't find information you need or have questions specifically related to you, call your primary care doctor.</p><p>"Your personal doctor should always be a resource for individual specific questions because they know best how to apply all the nuances retaining to your health, and how to incorporate all the other general [COVID-19] recommendations," Stukus said.</p><p><a href="https://www.eehealth.org/find-a-doctor/b/boyd-laura-b/" target="_blank">Dr. Laura Boyd</a>, primary care physician at Edward-Elmhurst Health Center in Elmhurst, Illinois, says her clinic receives a lot of calls about COVID-19.</p><p>"Most doctors' offices are receiving calls and answering questions, and doing phone or video visits to help clarify and/or order testing over the phone based on patients' symptoms. It is always best to call your doctor's office first instead of worrying about symptoms and waiting too long to seek treatment," she told Healthline.</p><p>If your primary care doctor has limited testing, she suggests looking on your state's public health website for available testing sites.</p><p>With a lot of unknowns related to this virus and disease, Boyd says many patients are feeling overwhelmed and anxious for a treatment.</p><p>"Unfortunately, there is no specific medication recommended for COVID for outpatient. There are a lot of ongoing studies with various drugs going on within the hospital setting. Patients should always contact their doctors about their specific symptoms as they can treat the symptoms that go along with COVID, but there is no cure," Boyd said.</p><p>While we wait for treatment and a vaccine, Hirsch, who treats patients hospitalized for COVID-19 complications on a daily basis, says everyone can do their part by washing hands, wearing a mask, and staying 6 feet apart.</p><p>"As an infectious disease doctor working in the hospital, I see the damage of the pandemic and the worst cases of what's happening. We are trying to get the best possible outcome and confronting this overwhelming biologic reality of this terrible epidemic the best we can," Hirsch said.</p><p>Everyone at home can help in the fight too, he adds.</p><p>"Follow information that is science- and evidence-based, and avoid that which is not," he said.</p>
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The nationwide horror at the killing of George Floyd by the Minneapolis police has triggered protests in 75 cities. People are demonstrating against the systemic racism that has made people of color targets of lethal actions by law enforcement. In response, elected officials and public health experts are walking a fine line of affirming the rights of protestors while simultaneously worrying that the protests will lead to a new wave of coronavirus infections.
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