ABOVE: © istock.com, design cells

Fans of the spy genre would probably agree that any worthy antagonist must have a certain flair, a mix of deceptiveness and manipulation laced with a dangerously intelligent mind. There are plenty of fictional villains who can be considered criminal masterminds and challenging forces to be reckoned with. 

Inside the human body, the immune system is confronted with a similar threat from microbial tricksters that seek to breach the body’s defenses to perpetuate their own survival. To move stealthily through their host’s body, these tiny troublemakers—fungi, bacteria, viruses, and parasites—have evolved strategies to conceal themselves from immunological surveillance. 

Over the years, researchers have persistently and ingeniously uncovered these deceptive tactics to determine strategies that can tip the balance in favor of the human host.

Plasmodium falciparum: A Parasite that Excels at Camouflaging

In the 19th century, physician and parasitologist Charles Louis Alphonse Laveran first identified Plasmodium parasites while examining blood samples of patients suffering from malaria. After Laveran’s discovery, researchers tried to chart the parasite’s life cycle. By allowing mosquitoes to feed on the blood of malaria-infected patients, physician Ronald Ross was the first to identify the parasites in the stomach of the insects and suggest that the malaria parasite is transmitted through mosquito bites.1  

Since then, the complex life cycle of these single-celled protozoa has captivated researchers around the world, including Weill Cornell Medicine microbiologist Kirk Deitsch. In the 1990s, Deitsch first learned about Plasmodium parasites while studying the mechanisms of gene regulation in mosquitoes under the supervision of entomologist and parasitologist Alexander Raikhel. At the time, researchers knew that some bacteria and protozoa, including Trypanosoma and Plasmodium, had the extraordinary ability to rapidly switch the molecules they exposed to the host’s immune system, a process known as antigenic variation.2,3 

A group of people in a laboratory. Lab equipment is seen on the bench.
Each year, Kirk Deitsch (in a blue shirt) visits different countries in Africa and teaches local students about the malaria parasite.
David Roos

Because malaria parasites hide inside red blood cells, their antigenic variation mechanism involves switching parasite-produced molecules on the surface of infected erythrocytes.4 In the particular case of P. falciparum—the deadliest Plasmodium species to cause malaria in humans—this phenomenon was mediated by the differential expression of a protein called P. falciparum erythrocyte membrane protein 1 (PfEMP1).5-7 Because Plasmodium-infected red blood cells deviate from the classic biconcave shape, they are more prone to be removed from circulation and destroyed by splenic clearance.8 “What the parasite does is put this protein PfEMP1 through the erythrocyte membrane,” Deitsch explained. “It serves as Velcro to stick [the cell] to the blood vessel wall, so it doesn't go through your spleen.” 

While Deitsch was a graduate student, a team of researchers led by physician scientist Thomas Wellems at the National Institute of Allergy and Infectious Diseases inadvertently stumbled upon a large and variable family of genes, the var gene family, which encoded the PfEMP1 protein.9 “Each parasite had 60 to 70 var genes, and each one encoded a different form of this protein,” said Deitsch, who first learned about these findings in a seminar that Wellems gave at his institution. “I thought that was the coolest puzzle in the world,” he recalled.

Motivated to solve this puzzle, Deitsch joined Wellems’ lab as a postdoctoral researcher in 1996. At that time, Wellems and his team were searching for the genes that allowed Plasmodium parasites to withstand antimalarial drugs, particularly chloroquine—a synthetic drug used to treat the disease since the 1960s.10 On his first day in Wellem’s lab, Deitsch recalled meeting the other team members, including Xin-zhuan Su, who was heading the chloroquine resistance study and had discovered the var genes. “He went to the freezer and came back with a box [that] was labeled GFH, and I said, ‘what does GFH stand for?’, and he said, ‘it stands for genes from hell,’” Deitsch recalled. “He was trying to find the chloroquine resistance gene and these things kept getting in the way and it made mapping chromosomes really hard. It was a nightmare for him.”

The parasites are using a very similar mechanism to what is done in higher eukaryotes in terms of epigenetic gene activation and silencing.

 —Kirk Deitsch, Weill Cornell Medicine 

In the following years, Deitsch delved into studying the regulation of P. falciparum antigenic switch. He and his colleagues found that spontaneous recombination events led to switches in var gene expression within a cluster of these genes in the parasite’s chromosome 12, a phenomenon that is not regulated by variations in the promoter sequence or changes in transcription factors.11 

In a subsequent study, the researchers investigated how P. falciparum expresses only one var gene at a time, a phenomenon called mutually exclusive expression. The team examined whether conserved introns in these genes could be a source of var promoter silencing. By transfecting P. falciparum with reporter constructs, they found that an intron sequence repressed the expression of a reporter gene under the control of a var promoter, suggesting a cooperation between non-coding sequences and promoter regions in the regulation of the mutually exclusive expression phenomenon.12  

As Deitsch continued to study antigenic variation in P. falciparum as a group leader at Weill Cornell Medicine, he was convinced that epigenetic mechanisms played a role in that process. Among the well-established epigenetic alterations, histone modifications were known to regulate how accessible genes were to the transcriptional machinery by loosening or tightening the histone-DNA interactions. Deitsch’s team looked at histone alterations in P. falciparum using a blasticidin drug-resistance marker gene to direct the expression of a single var gene and found that methylation of histone three acted as a mark of gene silencing in the parasite.13 Around the same time, other researchers also described the key roles of histone alterations in var gene silencing and activation.14,15 

Red blood cells infected with Plasmodium falciparum parasites.
Using specific stains, researchers can visualize P. falciparum parasites infecting red blood cells.
Evi Hadjimichael and Joseph Visone

“The parasites are using a very similar mechanism to what is done in higher eukaryotes in terms of epigenetic gene activation and silencing,” Deitsch said. 

Plasmodium species have a repertoire of var genes to actively alternate over the course of an infection; yet, how they know when to start the shift was a question that intrigued Deitsch. For years, researchers believed that malaria parasites had evolved an intrinsic rate of switching that matched the time it took their hosts to mount an effective antibody response, Deitsch explained. “We became interested in whether or not that was too simplistic [and if] the parasites do actually sense their environment,” he said.  

By depleting or supplementing the levels of nutrients in the parasites’ culture media used for the S-adenosylmethionine (SAM) metabolism, the main source of methyl for histone methylation, Deitsch and his team showed that changes in SAM availability influenced var expression in P. falciparum, suggesting that the parasites can sense changes in their environments.16

Although researchers have deciphered many aspects of the parasite’s life cycle and some of its tricks for immune evasion, the unicellular protozoan still holds many secrets. For Deitsch, one puzzling problem that remains unsolved is how the parasites change the regulation of the var genes as they move to their mosquito host or leap into erythrocytes for the first time. In collaboration with Photini Sinnis, a physician scientist at Johns Hopkins University, he now explores how malaria parasites know when to turn on var genes as they leave the liver, an organ the parasites use for their initial replication and development into another form, and venture into the bloodstream to infect red blood cells. “This is all fascinating stuff that we are beginning to develop tools to enable us to do this in detail, which we haven't been able to do in the past,” he said.

Intracellular Manipulation by Mycobacterium tuberculosis

Mycobacterium tuberculosis, the causative agent of tuberculosis, an infectious disease that commonly attacks the lungs and can be fatal if left untreated, has developed strategies to survive the hostile human immune system for tens of thousands of years.17 For Jennifer Philips, an infectious disease physician and researcher at Washington University in St. Louis, this long-term coevolution with humans makes M. tuberculosis a very unique bacterium. “There are very few bacteria that establish a kind of chronic infection the way it can, that can hide for really long periods of time and not be eliminated,” she said. “You can think of viruses that are like that, but when it comes to bacteria, [M. tuberculosis] is really the master of that.”

In the early 2000s, Philips sought to understand the interactions of the Mycobacterium and its host by investigating host factors that could influence the pathogen’s entry and survival in macrophages, a type of myeloid cell that is primarily targeted by this intracellular pathogen. So, she undertook a postdoctoral training under the joint supervision of Harvard University geneticist Norbert Perrimon and tuberculosis researcher Eric Rubin. 

Jennifer Philips, an infectious disease researcher and physician at Washington University in St. Louis, investigates Mycobacterium tuberculosis. She and Ekansh Mittal, an instructor in the same institution, wear laboratory coats and are seated. An image of bacterial cells can be seen in a computer screen on the background.
In her lab at Washington University in St. Louis, Jennifer Philips studies the interactions of M. tuberculosis and the host immune system.
Matt Miller

To gain a broad view of the host factors required for mycobacterial survival, Philips turned to a well-characterized system in Drosophila melanogaster that allowed her to perform a genome-wide RNA interference (RNAi) screen. She infected D. melanogaster S2 cells, which are macrophage-like cells, with Mycobacterium fortuitum, a M. turberculosis-related species. To track bacterial growth in the cells, she developed mutants in which the expression of a green fluorescent protein was under the control of a macrophage-activated promoter, a region of DNA found in genes that are preferentially expressed when the bacteria are inside macrophages. She found that RNAi knockdown of host genes involved in vesicle trafficking and cytoskeleton organization reduced M. fortuitum infection.18 In a follow-up study, Philips and her colleagues explored another subset of factors identified in the initial screen, which included members of the endosomal sorting complex required for transport (ESCRT) machinery—a set of protein complexes involved in the sorting and trafficking of ubiquitylated proteins from endosomes to lysosomes.19 Knockdown of components of the ESCRT machinery in S2 fruit fly cells and mammalian macrophages created a phagosome compartment more permissive for mycobacterial growth, revealing a previously unknown role of the ESCRT machinery in bacterial trafficking.20 

There are very few bacteria that establish a kind of chronic infection the way it can, that can hide for really long periods of time and not be eliminated. You can think of viruses that are like that, but when it comes to bacteria, [M. tuberculosis] is really the master of that.

 —Jennifer Philips, Washington University in St. Louis 

In the years that followed, Philips turned her attention to the pathogen, looking for virulence factors that could contribute to its ability to disrupt the ESCRT machinery and escape intracellular death. She focused on M. tuberculosis type VII secretion systems, which send substrates out of the cell and are key to the bacterial pathogenesis.21 By looking at interactions of mycobacterium-secreted molecules and host proteins, they found that EsxH and EsxG, which are effector proteins secreted by the type VII secretion system ESX-3, interacted with the ESCRT machinery and disrupted the delivery of the pathogen to lysosomes.22 “By targeting the ESCRT machinery, [EsxH and EsxG] have a really wide array of effects on the macrophage cells, and part of that is to prevent the normal maturation of the phagosome,” Philips said.

Since M. tuberculosis sets up home inside antigen-presenting cells such as macrophages and dendritic cells, the bacilli are poised to disrupt the crosstalk between the innate and adaptive immune responses.23 Macrophages and dendritic cells present pathogen-related antigens to CD4 T cells via the major histocompatibility complex class II (MHC-II).24 The ESCRT machinery plays a role in intracellular sorting and trafficking, so Philips and her colleagues wondered if the Mycobacterium effectors could also affect MHC-II antigen presentation. Using bone marrow-derived macrophages, the researchers showed that the ESCRT machinery facilitates antigen processing and that the M. tuberculosis EsxH-EsxG complex impairs antigen presentation.25 

“It's that interaction between macrophages and T cells that is really part of the fundamental problem in the host’s immune ability to clear [M. tuberculosis],” Philips explained. “Because even if you make really good T cells, they are not really interacting with the infected macrophages appropriately. They don't really exert their antimicrobial function.”

More recently, Philips and her team have turned their attention to other effectors the bacilli have in their arsenal, including the secreted CpsA protein, which is a member of a protein family essential for cell wall maintenance in Gram positive bacteria.26 Philips’ team found that CpsA was key for M. tuberculosis to avoid a non-canonical autophagy pathway by impairing the generation of reactive oxygen species in the phagosome and its maturation into antibacterial phagosome.27 

Cells infected with the pathogen Mycobacterium tuberculosis.
Mycobacterium tuberculosis invades immune cells and uses an array of tactics to avoid intracellular destruction.
Jully Sadadiwala

Since many different types of macrophages are infected by M. tuberculosis throughout the course of the disease, Philips is exploring how the mycobacterial effectors modulate these distinct cell populations. In a study published early this year, her team profiled the lung cells of M. tuberculosis-infected mice and showed that CpsA is essential for the mycobacterial dissemination from tissue-resident macrophages to myeloid cells that are recruited to the infection site and to the lung interstitium.28

According to Philips, a better understanding of the pathogen’s ingenious mechanisms may not only help scientists develop more effective therapeutics to fight the disease, but also provide insights into how the mycobacterium manages different modes of attack during an infection. “[M. tuberculosis] has to do very different things to maintain the infection dynamic. It has to be kind of stealth initially, and we don't even know people are infected. And yet to transmit to another individual, it has to cause tremendous tissue damage and be really hyper inflammatory,” she explained. “That's why I feel it really understands the immune system in a way we don't. It knows how to be stealth and quiet and then how to create a lot of destruction when it is going to transmit.”

HIV, a Controller of Host Molecules

When it comes to microbial stealth agents, viruses also employ cunning strategies to fool the immune system defenses. For more than three decades, Olivier Schwartz, a virologist at the Pasteur Institute, has been intrigued by the tactics used by the human immunodeficiency virus (HIV).

A retrovirus that attacks key players of the immune system, including antigen-presenting cells and, most notably, CD4 T cells, HIV weakens the immune system and causes acquired immunodeficiency syndrome (AIDS) at the most advanced stage of infection. More than 40 years after the Centers for Disease Control and Prevention published the first reports of a rare and deadly disease, AIDS has become a manageable chronic health condition with the use of antiretroviral treatments. Yet it remains an incurable disease.

In the late 1980s, Schwartz began to study HIV-1, the most common type of HIV, as an intern scientist in the laboratory of Pasteur Institute virologist Luc Montagnier, who had helped discover the virus a few years earlier. At the time, the team searched for novel drugs that could battle HIV-1, and Schwartz’s work focused on testing some of these potential antiviral compounds. As Schwartz began his graduate studies, he joined the laboratory of Pasteur Institute researchers Olivier Danos and Jean-Michel Heard and delved into the pathogen’s biology, focusing on the proteins encoded by the small viral genome.  

Olivier Schwartz, a virologist at the Pasteur Institute, studies HIV and other human pathogenic viruses. He wears a gray pullover and glasses.
Virologist Olivier Schwartz explores the biology of pathogenic viruses in his lab at the Pasteur Institute.
Pasteur Institute

Specifically, he investigated the negative factor (Nef) protein, a molecule the virus expresses early in the viral cycle and primarily localizes in the cytoplasm of the infected cell. Previous work on the simian immunodeficiency virus (SIV) suggested that Nef was key for maintaining high viral loads and viral pathogenicity in rhesus macaques.29 Researchers also showed that HIV-1 downregulated the expression of the major histocompatibility complex class I (MHC-I), which along with MHC-II, plays a central role in antigen presentation.30,31 To examine whether Nef contributed to viral survival by downregulating MHC-I, Schwartz and his colleagues compared the expression of this protein in cells infected with control and nef mutant viral particles. Nef expression downregulated MHC-I on the surface of cells by stimulating the internalization and later degradation of the molecule.32 “At that time, this was original. It had not been described before that a viral protein was able to turn down this important immune molecule to protect infected cells,” Schwartz said. 

A few years later, as a group leader at the Pasteur Institute, Schwartz collaborated with Philippe Benaroch, an immunologist at the Curie Institute, and found that HIV-1 Nef reduced the expression of mature MHC-II molecules, revealing another viral trick to block the induction of a proper antiviral response.33 

Schwartz’s team also found that the disruption of intracellular trafficking caused by Nef extended beyond its effects on MHC molecules. In the mid-2000s, the researchers explored if the protein could also muddle the formation of immunological synapses, specialized structures that allow antigen-presenting cells and T cells to communicate and generate an effective T cell response against an infectious agent.34 Using wild type and nef-deficient HIV-1 particles, the researchers showed that Nef induced the formation of abnormal immunological synapses that lacked T cell receptors as well as other molecules important for the structure’s formation and function.35 

Immune cells are labeled with a red marker. HIV particles (green) from an infected cell are transferred to an uninfected cell via direct cell-to-cell contact.
HIV particles (green) move from one cell to another by direct contact of an infected cell with an uninfected neighboring cell (red).
Olivier Schwartz

“HIV or SIV are really in the heart of the immune system because they infect the cells which are normally there to combat, to fight infected cells,” Schwartz said. “By perturbing this network of interactions, [the virus] facilitates the establishment of a persistent infection, and that's one of the reasons why it's very difficult to get rid of [it].” 

Free viral particles are often thought to be the primary route by which a virus gets transmitted to other cells; however, HIV-1 particles can also be transferred by direct contact between infected and neighboring uninfected cells. This mode of transmission involves the formation of virological synapses, which are contact zones between the cells that concentrate the budding viral particles and the receptors the virus binds to.34 By examining HIV-1 cell-to-cell transfer, Schwartz and his team showed that Nef increases the localization of group-specific antigen (gag), a main viral structural protein, in the cell membrane while also promoting viral transfer by direct cell-to-cell contacts.36 “For HIV, and other viruses as well, I think the infectious entity is more the infected cell itself rather than the cell-free viral particles,” Schwartz explained. “Both are important, but once a cell is infected, it can produce a lot of viral particles, and it will move. It’s like a boat carrying a lot of viral passengers in a way.” 

For HIV, and other viruses as well, I think the infectious entity is more the infected cell itself rather than the cell-free viral particles. Both are important, but once a cell is infected, it can produce a lot of viral particles, and it will move. It’s like a boat carrying a lot of viral passengers in a way.

 —Olivier Schwartz, Pasteur Institute

Despite significant advances in understanding HIV biology and the development of new therapeutics to manage AIDS, there are still unresolved questions, according to Schwartz. A puzzling and challenging topic is the latent viral reservoir, which consists of HIV-infected cells that linger in the body without actively producing new viral particles. An area of research that Schwartz is actively investigating is how other pathogens might contribute to HIV pathogenesis. “We know that the virus prefers to replicate in active cells, and lymphocyte activation can be triggered by other microbes,” he explained. Recently his team found that the presence of some bacteria, including Escherichia coli and Acinetobacter baumannii, activated T cells, which in turn showed greater HIV-1 replication.37 “This is a field of research which deserves further investigation,” Schwartz said.

How to Get Away from the Immune System

The immune system is highly trained to detect and eliminate any potential threat to the human body. While years of evolution have turned this system into a pathogen-killing machine, the microbes it fights have also evolved intricate strategies to evade it.


A Parasite and the Art of Cloaking

On the left, several red blood cells are shown sticking to blood vessel walls, with grey malaria parasites within them. On the right, a graph shows how parasitemia rises and falls over time as the parasite uses different forms of PfEMP1.
modified from © istock.com, Shivendu Jauhari, Irfan Setiawan, Eranicle

1) The malaria parasite Plasmodium falciparum expresses the protein PfEMP1 on the surface of erythrocytes to adhere the cells to blood vessel walls and escape clearance by the spleen.

2) PfEMP1 can be detected by immune cells. Through the process of antigenic variation, P. falciparum expresses different versions of it and escapes immune recognition.


Controlling the Enemy Within

On the left, Mycobacterium tuberculosis bacteria enter a macrophage and pathways by which the bacteria avoid destruction, and how they disrupt communication between the macrophage and a T cell (shown on the right) are depicted.
modified from © istock.com, ttsz

3) Inside macrophages, Mycobacterium tuberculosis dodges intracellular degradation by secreting virulence factors. Two effectors, EsxH and EsxG, inhibit the function of the ESCRT machinery, impairing the maturation of bacteria-carrying phagosomes. 

4) Another Mycobacterium virulence factor, CpsA, disrupts another degradation pathway and blocks the activity of NADPH oxidase, impairing the destruction of the bacteria.

5) By affecting the normal function of ESCRT, M. tuberculosis EsxH-EsxG complex also disturbs the process of antigenic presentation via the MHC-II molecule.


A Viral Manipulator

On the left, HIV disrupts surface expression of MHC proteins in a T cell; HIV also impairs communication between T cells and an antigen-presenting cell, shown on the right.
modified from © istock.com, ttsz, bombuscreative  

6) To stay hidden inside lymphocytes, HIV-1 expresses viral factors such as the negative factor (Nef) protein. In the infected cell, Nef downregulates the expression of MHC-I and MHC-II on the cell surface, impairing the presentation of viral antigens.

7) Nef also disrupts the proper formation of immunological synapses, the points of communication between T cells and antigen-presenting cells. 


A Temporary Fungal Shield

on the left, a pink Candida albicans cell is shown. A section of the cell wall is enhanced to show how the beta-glucans, shown in green, are covered by mannans, shown in blue. On the right, macrophages recognize beta-glucans.
modified from © istock.com, ttsz, KKT Madhusanka

8) In Candida albicans, beta-glucans are a major target for immune detection by macrophages, which are one of the first lines of immune defense. The fungus covers its beta-glucans with a layer of mannans, shielding them from macrophage detection to prolong their stay in the host.  

See full infographic: WEB | PDF

Candida albicans: A Metamorphic Microbe

Fungi, for the most part, inhabit the human body as commensals, but different factors can disrupt this harmonious relationship, leading to severe fungal infections that are estimated to claim the lives of 2.5 million people per year worldwide.38 One such example is Candida albicans, a yeast commonly found on the human skin, mouth, gastrointestinal tract, and vagina. “Most of us, at some stage of our life, are absolutely harmlessly colonized by Candida [albicans]. So, it's really intriguing to know how it can be a Dr. Jekyll and Mr. Hyde organism, living in harmony most of the time, and then, under other conditions, being a genuinely life-threatening disease,” said Neil Gow, a medical mycologist at the University of Exeter who has delved into the fungi kingdom for more than 40 years.

Gow’s interest in the mysteries that lie beyond what is visible to the naked eye motivated him to enter the field of microbiology, and it was during his graduate studies under the supervision of University of Aberdeen biological chemist Graham Gooday, that he turned his attention to C. albicans. “I was sharing a lab with people who could barely see their microbes because they were so tiny, and they grew so slowly. Candida grows really fast, and it does lots of things under the microscope,” said Gow. 

Gow was particularly captivated by the fungal cell wall, a dynamic layered structure engineered so that the innermost layer contains conserved structural elements, while the outermost layer is more variable and tailored to the specific needs of the organism.39 “The fungal cell wall is really to me the defining organelle of a fungus,” he said. 

Because it is composed of molecules not found in the human body, the fungal cell wall becomes a primary target of the immune system, in particular macrophages, which are among the first immune cells sent into the trenches to fight invasive fungi. Gow and his colleagues wanted to better understand the interactions between the fungal cell wall and these immune system frontline fighters. By using C. albicans mutants that lacked components in the biosynthesis of mannans, which are polymers of the sugar mannose located in the outermost part of cell wall, they found that the mutants were more often engulfed by macrophages than wild type yeasts, suggesting that mannans in the C. albicans cell wall help the fungus evade these immune cells.40 

Mannans in the fungal cell wall can shield other molecules in the inner layer of the structure from immune detection. That’s the case of the beta-glucans, polysaccharides which are pathogen-associated molecular patterns (PAMPs) that elicit a strong immune response upon detection by specific macrophage receptors.41 By investigating this mannan masking phenomenon in C. albicans, Gow and his colleagues found that depletion of a specific type of mannan, O-mannan, exposed the beta-glucans at the fungal surface, facilitating macrophage recognition and phagosome maturation inside this innate immune cell.42  

According to Gow, the fungal cell wall is also highly regulated, and changes in the environment can cause the structure to remodel. In the specific case of beta-glucan exposure, Gow and others showed that host cues such as low levels of oxygen, exposure to acidic environments, or lactate, which represent conditions that the fungus can find in some of the niches it inhabits in the human body, induce beta-glucan remasking.43-45 “[The fungal cell wall] is something that monitors itself constantly, and changes itself to protect itself from a changing environment,” Gow noted.

Mannans mask PAMPs from macrophage detection, but that does not mean they are invisible to all immune cell types. Monocytes, which are also recruited to the infection site, express pattern recognition receptors that allow them to spot the mannan component of the fungal cell wall.46 The mannan shielding/activator conundrum intrigued Gow’s team who explored this problem by using four yeast-like fungi that lacked an enzyme important for mannan synthesis. While macrophages showed enhanced response to the mannan mutant yeasts, likely by recognizing the beta-glucans exposed in the absence of the mannan coat, monocytes had an attenuated response to these mutants, suggesting that mannans are immune agonists for these immune cells.47 Exploring mannan recognition all the way down to the molecular level is one of Gow’s current goals. “We’re trying to find exactly what type of mannans are seen by what type of mannan recognition immune receptors, trying to understand why there are so many different classes of receptors,” he explained. 

Although Gow and other fungi researchers have relentlessly tried to find effective ways to prevent and fight fungal diseases, he also recognizes how humans have benefited from their relationship with these organisms. “Every one of us uses a fungal product every day of our lives. It could be in bread; it could be in fermented foods. If you've got high blood pressure, you're going to have a statin, and if you've got a bacterial infection, you're going to have penicillin,” he noted. “Fungi are amazing organisms and we're only trying to kill them because we're vulnerable to them, but we still have to have a reverence for these organisms because they're special.” 

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