What part of the immune system fights fungi?

Antifungal immune responses: emerging host–pathogen interactions and translational implications

Understanding the complex and highly dynamic interactions between fungi and host cells in a tissue-specific manner is crucial to facilitate the development of new therapeutic approaches to infections. Here, we discuss recent studies that are revealing the mechanisms underlying this context-dependent interplay.

The mycobiome, fungal infections, and immunity

Fungi are common inhabitants of human barrier surfaces such as the oral cavity, skin, vagina, gut, and lungs. Altered immune status, usually due to treatment with immunosuppressive drugs and sometimes caused by inherited deficiencies in host defense, leads to increased susceptibility to fungal infections. Invasive fungal infections are associated with high mortality rates with an estimated 1.5 million deaths globally each year. Mucosal infections are more prevalent than invasive infections and are a major cause of morbidity. In contrast to bacterial and viral infections, an effective vaccine against fungal infections has not been developed, and currently available antifungal drugs are only partly successful in treating patients with invasive fungal infections. Immunological and genetic studies indicate a crucial role of human immune defects in fungal infections. Therefore, identification of appropriate prophylactic and immunotherapeutic targets has been considered the most promising strategy to overcome morbidity and mortality.

Most invasive fungal infections are caused by species from three genera: Candida, Aspergillus, and Cryptococcus. These fungi can exist in two morphological forms: yeasts (unicellular forms that reproduce asexually by conidia formation) and hyphae (multicellular forms with branching, tubular filaments), which have different cell wall compositions. The hyphal morphotype is usually associated with tissue invasion whereas the conidial form is associated with colonization, which suggests differential host recognition and explains the contrast in virulence.

Fungal pathogens present a variety of pathogen-associated molecular patterns (PAMPs) that may require a unique set of pattern recognition receptors (PRRs) from host cells to recognize and activate distinct downstream immune responses (Table 1). Innate immune cells such as dendritic cells, monocytes, macrophages, and neutrophils are known to express an array of PRRs to recognize fungal infections, to induce protective responses, and to activate adaptive immunity. Roles for different PRRs such as C-type lectin receptors (CLRs), Toll-like receptors (TLRs), and NOD-like receptors (NLRs) in sensing fungal infection and triggering appropriate anti-fungal responses have been established (reviewed in [1]). However, the diverse morphological adaptations (such as conidial and hyphal forms) among fungal pathogens during their interaction with the host immune system, in different tissue compartments and/or different environmental conditions, have hampered efforts to identify therapeutic targets. Recent genetic, genomic, and experimental studies are providing insights into the underlying context-dependent immune mechanisms against fungal infections and the evasion strategies utilized by fungal pathogens, as well as novel host and pathogen targets for the development of potential therapies.

Table 1 Human pattern recognition receptors and cell types involved in antifungal immune responses (reviewed in [1])

Host–pathogen interactions in antifungal immunity

The cell wall of Aspergillus fumigatus contains an immunologically active ligand called melanin. In an elegant study, Stappers et al. [2] showed that the lectin receptor MelLec, encoded by the CLEC1A gene, is a melanin-sensing CLR, using mouse models and human subjects. This receptor recognizes the naphthalene-diol unit of 1,8-dihydroxynaphthalene (DHN)-melanin present only in conidial spores of A. fumigatus and other fungi containing DHN-melanin, but not Candida albicans or Saccharomyces cerevisiae, which highlights the importance of microbial ligand specificity. MelLec is specifically expressed in mouse endothelial cells, whereas in humans it is ubiquitously expressed in endothelial and myeloid cells. Importantly, a single nucleotide polymorphism (SNP) in the CLEC1A gene of human donors that resulted in an amino acid polymorphism (Gly26Ala) in MelLec increased the risk of disseminated Aspergillus infections in hematopoietic stem-cell transplant recipients, but this risk was not dependent on recipient SNP genotype. It will be interesting to test whether this polymorphism plays a role in distinct fungal infections in different tissues, which may help to address the question of whether the protection is driven by a pathogen- and/or tissue-specific function of this receptor. Pentraxin 3 (PTX3) is a secreted PRR that is also crucial for host defense against A. fumigatus [3]. Recently, polymorphisms in the human PTX3 gene have also been associated with aspergillosis in patients undergoing hematopoietic stem cell transplantation [4]. Furthermore, downregulation of PTX3 in dendritic cells caused by impaired calcineurin signaling results in higher susceptibility of mice to invasive pulmonary aspergillosis [5]. Administration of PTX3 restores antifungal host responses in humans and mice, but more studies are needed to understand the precise mechanism underlying how PTX3 coordinates the host response against aspergillosis in humans.

Shlezinger et al. [6] unraveled a novel mechanism that underlies how neutrophils in the lung kill A. fumigatus conidia, and, conversely, how A. fumigatus evades this process. Neutrophils trigger fungal caspase-dependent programmed cell death in the conidia by producing NADPH oxidase, which results in the production of reactive oxygen species and fungal cell death. To evade host-induced programmed cell death A. fumigatus expresses the gene AfBir1. This gene is homologous to the human Survivin gene, which contains a BIR domain that is involved in the suppression of apoptosis by caspase inhibition. These findings highlight the potential for identifying drug targets in the pathogen genome, and suggest that inhibition of A. fumigatus AfBir1 could be used to treat invasive aspergillosis, to induce programmed cell death in conidia and improve host survival.

In the human gut, CLRs dectin-1 and dectin-3 are PRRs that have been shown to be important in mediating anti-fungal responses to intestinal fungi (gut mycobiota). Leonardi et al. [7] determined the cell type involved in the regulation of anti-fungal immunity in the intestine. Upon colonization of mouse intestine with C. albicans, several fungal PRRs such as dectin-1, dectin-2, and mincle were more highly expressed in gut-resident CX3CR1 + mononuclear phagocytes (MNPs) than in dendritic cells. Dendritic cells were previously shown to be important for host defense against fungal infections in the lung. Specific depletion of CX3CR1 + MNPs in mice resulted in a reduction in anti-fungal Th17 cells and in IgG antibody responses against intestinal C. albicans but not against systemic infection. Thus, CX3CR1 + MNPs were specifically involved in innate and adaptive immune responses to intestinal fungi. These findings underscore the importance of tissue-specific cellular functions in fungal infections. Leonardi et al. [7] also investigated the effect of genetic variations in the human CX3CR1 gene on immunity to fungal infections in patients with inflammatory bowel disease. It is conceivable that because of the immunosuppression treatment strategy used for patients with inflammatory bowel disease, there is an increased risk of intestinal and extra-intestinal fungal infections. A coding polymorphism in CX3CR1 in patients with Crohn’s disease was associated with impaired ability to produce antibodies against multiple gut fungal species. These findings further identified a role for CX3CR1 + MNPs in antifungal immune responses during inflammatory disease. Whether targeting specific cell types such as CX3CR1 + MNPs to generate effective antibody responses against pathogenic fungi would be effective in Crohn’s disease patients remains a question for future studies.

Regulation of the antifungal immune response involves coordinated function of many different cell types. Neutrophils and monocytes, which have essential roles in building and modulating the innate immune response, are particularly important in eliminating fungal pathogens, and their roles in regulating interferon (IFN) responses have also been highlighted recently. Using an in vitro infection model and genomics approach, we and others previously showed that the type I interferon (IFN α and β) pathway is strongly activated in response to C. albicans infection in human peripheral blood mononuclear cells (which included monocytes and lymphocytes but not neutrophils) [8]. Also, a recent study by Espinosa et al. [9] uncovered another interferon pathway, namely type III IFNs (IFN-λs), as a crucial regulator of antifungal neutrophil responses against A. fumigatus. The study also emphasized the importance of context-dependent cellular communication, in which a subset of pulmonary monocytes that express chemokine receptor CCR2 (CCR2+ monocytes) together with neutrophils regulate both type I and type III interferon responses for efficient antifungal responses. In contrast to the antifungal role of gut-resident CX3CR1+ MNPs identified by Leonardi et al. [7], the CCR2+ pulmonary monocytes were important for the antifungal response in the lung [9]. Although the exact cell type that produces IFN-λ is still unknown, observations from survival studies in CCR2-depleted mice upon treatment with IFN-α and IFN-λ cytokines suggest that recombinant cytokine therapies can enhance protective IFN responses and antifungal immunity and could provide potential therapeutic benefits [9].

Conclusions and future directions

Recent studies have provided important insights into the mechanistic basis for the cellular and organ specificity of host immune responses against fungi, the receptors and pathways involved, and how alterations in these pathways can confer susceptibility to fungal infections in humans. Furthermore, cytokine responses in human peripheral blood mononuclear cells against different fungal and bacterial stimulations have been shown to be strongly dependent on cell type and pathogen type [10]. However, much remains to be discovered about these mechanisms.

Considering the context-dependent regulation of antifungal responses, future studies should focus on systems approaches to comprehensively identify the specific cell types and host and pathogen factors that are involved in orchestrating effective antifungal host responses. Nevertheless, these recent discoveries are stepping-stones towards the design and introduction of effective adjuvant immunotherapy for the treatment of fungal infections.

Abbreviations

Naphthalene-diol unit of 1,8-dihydroxynaphthalene (DHN)-melanin

Immune response

The immune response is how your body recognizes and defends itself against bacteria, viruses, and substances that appear foreign and harmful.

Information

The immune system protects the body from possibly harmful substances by recognizing and responding to antigens. Antigens are substances (usually proteins) on the surface of cells, viruses, fungi, or bacteria. Nonliving substances such as toxins, chemicals, drugs, and foreign particles (such as a splinter) can also be antigens. The immune system recognizes and destroys, or tries to destroy, substances that contain antigens.

Your body’s cells have proteins that are antigens. These include a group of antigens called HLA antigens. Your immune system learns to see these antigens as normal and usually does not react against them.

Innate, or nonspecific, immunity is the defense system with which you were born. It protects you against all antigens. Innate immunity involves barriers that keep harmful materials from entering your body. These barriers form the first line of defense in the immune response. Examples of innate immunity include:

• Cough reflex
• Enzymes in tears and skin oils
• Mucus, which traps bacteria and small particles
• Skin
• Stomach acid

Innate immunity also comes in a protein chemical form, called innate humoral immunity. Examples include the body’s complement system and substances called interferon and interleukin-1 (which causes fever).

If an antigen gets past these barriers, it is attacked and destroyed by other parts of the immune system.

Acquired immunity is immunity that develops with exposure to various antigens. Your immune system builds a defense against that specific antigen.

Passive immunity is due to antibodies that are produced in a body other than your own. Infants have passive immunity because they are born with antibodies that are transferred through the placenta from their mother. These antibodies disappear between ages 6 and 12 months.

Passive immunization may also be due to injection of antiserum, which contains antibodies that are formed by another person or animal. It provides immediate protection against an antigen, but does not provide long-lasting protection. Immune serum globulin (given for hepatitis exposure) and tetanus antitoxin are examples of passive immunization.

The immune system includes certain types of white blood cells. It also includes chemicals and proteins in the blood, such as antibodies, complement proteins, and interferon. Some of these directly attack foreign substances in the body, and others work together to help the immune system cells.

Lymphocytes are a type of white blood cell. There are B and T type lymphocytes.

• B lymphocytes become cells that produce antibodies. Antibodies attach to a specific antigen and make it easier for the immune cells to destroy the antigen.
• T lymphocytes attack antigens directly and help control the immune response. They also release chemicals, known as cytokines, which control the entire immune response.

As lymphocytes develop, they normally learn to tell the difference between your own body tissues and substances that are not normally found in your body. Once B cells and T cells are formed, a few of those cells will multiply and provide «memory» for your immune system. This allows your immune system to respond faster and more efficiently the next time you are exposed to the same antigen. In many cases, it will prevent you from getting sick. For example, a person who has had chickenpox or has been immunized against chickenpox is immune from getting chickenpox again.

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The inflammatory response (inflammation) occurs when tissues are injured by bacteria, trauma, toxins, heat, or any other cause. The damaged cells release chemicals including histamine, bradykinin, and prostaglandins. These chemicals cause blood vessels to leak fluid into the tissues, causing swelling. This helps isolate the foreign substance from further contact with body tissues.

The chemicals also attract white blood cells called phagocytes that «eat» germs and dead or damaged cells. This process is called phagocytosis. Phagocytes eventually die. Pus is formed from a collection of dead tissue, dead bacteria, and live and dead phagocytes.

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IMMUNE SYSTEM DISORDERS AND ALLERGIES

Immune system disorders occur when the immune response is directed against body tissue, is excessive, or is lacking. Allergies involve an immune response to a substance that most people’s bodies perceive as harmless.

Vaccination (immunization) is a way to trigger the immune response. Small doses of an antigen, such as dead or weakened live viruses, are given to activate immune system «memory» (activated B cells and sensitized T cells). Memory allows your body to react quickly and efficiently to future exposures.

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COMPLICATIONS DUE TO AN ALTERED IMMUNE RESPONSE

An efficient immune response protects against many diseases and disorders. An inefficient immune response allows diseases to develop. Too much, too little, or the wrong immune response causes immune system disorders. An overactive immune response can lead to the development of autoimmune diseases, in which antibodies form against the body’s own tissues.

Complications from altered immune responses include:

• Allergy or hypersensitivity
• Anaphylaxis, a life-threatening allergic reaction
• Autoimmune disorders
• Graft versus host disease, a complication of a bone marrow transplant
• Immunodeficiency disorders
• Serum sickness
• Transplant rejection

Alternative Names

Innate immunity; Humoral immunity; Cellular immunity; Immunity; Inflammatory response; Acquired (adaptive) immunity

WHO releases list of threatening fungi. The most dangerous might surprise you

Aspergillus fumigatus can infect the lungs, causing pneumonia-like symptoms that can progress into more severe sickness.

BSIP/Education Images/Universal Images Group via Getty Images

The idea of deadly fungi might conjure up images of poisonous red mushroom caps with distinctive white spots – or sneaky false morels that can turn a fun day of foraging into an evening of gastrointestinal distress.

But in reality, the most deadly fungi on the planet are practically invisible to the human eye!

The World Health Organization, in response to the rising threat of invasive fungal disease, released a list of priority fungal pathogens on Oct. 25 – and the most dangerous ones might surprise you. They’re all microscopic fungi, some of which have the potential to kill.

«Fungi are the ‘forgotten’ infectious disease. They cause devastating illnesses but have been neglected so long that we barely understand the size of the problem,» said Dr. Justin Beardsley, of the University of Sydney Infectious Diseases Institute, in a statement. Dr Beardsley was among the researchers supporting the WHO Fungal Priority Pathogens List’s development.

The priority list breaks down 19 of the most common fungal pathogens into three priority tiers based upon surveys and discussions with fungal infectious disease experts. The most dangerous is the «critical group,» which contains just four fungal pathogens: Cryptococcus neoformans, Aspergillus fumigatus, Candida albicans and Candida auris.

Cryptococcus and Aspergillus are both invasive fungi that can infect the lungs, causing pneumonia-like symptoms that can progress into more severe sickness. Candida albicans normally lives on the skin and inside the body without causing any problems. But if it starts to grow out of control, it can result in thrush of the mouth and throat or a vaginal yeast infection, also known as vaginal candidiasis. Candida auris is an emerging fungal threat, with very little known about it so far. But it’s often multidrug resistant and has caused serious outbreaks in healthcare facilities.

The ranking of fungal pathogens was decided by experts who weighed the impact of the fungal disease on public health and how much research and development has been given to the fungus so far.

The list was inspired by and follows in the footsteps of the 2017 Bacterial Priority Pathogens List, which the WHO used to help direct resources to bacterial infections that were the most under-researched and posed the greatest threats to global health. The hope is that now with the release of the Fungal Priority Pathogen List, policymakers will have guidelines in place helping them to direct resources toward dealing with the highest priority invasive fungal pathogens.

Infectious fungi are opportunists

While many of us think that most fungi out there are dangerous (with a small minority being edible), it turns out that most fungi don’t affect people at all. A recent study estimates that of the 150,000 fungal species described, only about 200 of them are infectious to people.

Those fungi that are infectious are often opportunistic pathogens – meaning we live with or near them all the time, but they only cause an infection in people who have weakened immune systems.

Take Aspergillus fumigatus, for example. It’s a relatively common fungus that can be found in decaying leaf litter nearly everywhere. Michelle Momany, a fungal researcher at the University of Georgia who studies Aspergillus, says that current research estimates that «every one of us inhales between 10 and 100 Aspergillus spores a day.»

The way that invasive fungal infections spread is very different from other infectious diseases. «These fungal infections, when you get them, it’s not from another person, you get them from the environment,» says Momany, who was not involved in the creation of the priority list.

For most people, this isn’t a big deal, but for others it could be deadly. «While an intact human immune system can easily fend off these fungal pathogens, those who are immunocompromised can’t, which might lead to a clinical infection,» Momany says.

The burden of infections

Despite the fact that many of these fungal infections are relatively common, the WHO report says a lack of data means it’s impossible to estimate the exact burden these diseases have on the global population.

The World Health Organization’s first-ever Fungal Priority Pathogens List breaks down 19 of the most common fungal pathogens into three priority tiers. World Health Organization hide caption

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World Health Organization

The World Health Organization’s first-ever Fungal Priority Pathogens List breaks down 19 of the most common fungal pathogens into three priority tiers.

World Health Organization

«Some of the best estimates out there say at least 1.5 million deaths a year are caused by invasive fungal infections. That’s on the same order as malaria. But people don’t think about fungal diseases in the same way,» says Momany.

Momany suggests that part of the issue is a lack of awareness on the part of clinicians, and not having the proper diagnostic tools might mean fungal infections aren’t discovered when a patient comes in with an infection. «Oftentimes [fungal diseases] are diagnosed on autopsy, which leads to the problem of them being underreported,» she says.

But the release of this priority list might help bring more attention and resources to creating new diagnostic tools, new treatments, and better training for clinicians. Dr. Orla Morrisey, co-chair of the Australia and New Zealand Mycoses Interest Group, said in a statement that, «this project has really focused the global mycology community on the task ahead.»

Antimicrobial resistance

The release of the list comes on the heels of an ever-growing number of invasive fungal diseases along with antimicrobial resistance becoming more common in invasive fungi.

WHO Assistant Director General of Antimicrobial Resistance, Dr. Hanan Balkhy, says, «Emerging from the shadows of the bacterial antimicrobial resistance pandemic, fungal infections are growing, and are ever more resistant to treatments, becoming a public health concern worldwide.»

One of the first tools that clinicians turn to when fighting a fungal infection are a class of antifungal drugs called azoles. But as usage has increased, invasive fungal pathogens have adapted and become resistant, just like many bacterial diseases have become resistant to antibiotics.

Unlike bacterial resistance to antibiotics though, the source of this antifungal resistance can be partially explained by environmental usage of antifungals. «One of the major fungicides used to protect crops from fungi is an azole. It’s now become pretty clear that agricultural use is driving some of the clinical resistance,» says Momany.

Morrisey calls for further investment into basic research, saying that, «this is the key to developing new drugs and diagnostic tests,» which might help detect and treat antifungal resistant infections.

Hopefully, the release of the priority list will bring more attention and resources to dealing with these invasive fungal pathogens. Momany says, «What’s great about [the release of the priority list] is to have it all pulled together now in a way that can inform policy. Having the World Health Organization tracking it now and bringing attention to it is just huge.»

• antimicrobial resistance
• fungi
• World Health Organization
• Global Health