Why Fungi Not Associated Mutualistically With Humans Assignment

Assignment Task

Abstract

Fungi are ubiquitous in the environment. Humans and fungi can coexist like some bacteria in human body but fungi can never have a mutualistic connection with humans. It is due to the absorptive mode of nutrition of the fungus which requires it to absorb human blood (as a source of carbon) to meet its nutritional needs. Blood containing white blood cells naturally serve as the first line of defence against foreign invaders in human body. A fungus fulfils four criteria to invade human’s i.e. heat resistance, locomotion through or around host barriers, lysis and absorption of carbon from human cells, and resistance to host immunity. Fungal invasion turns into infections in immuno-compromised persons and may be superficial, dermatophytic, subcutaneous and systemic and cause mild to life-threatening problem. This review aims to describe how the innate immune system and certain white blood cells combat fungi and prevent them from forming mutualistic association with humans.

Introduction

Fungi are ecologically and biologically varied organisms. They are heterotrophs that absorb their nutrients from external sources using one of three primary approaches: saprobic, parasitic, or mutualistic. Saprobic organisms obtain their energy by breaking down organic substances like glucose, cellulose, lignin, chitin, and keratin using enzymes. Parasitic forms get their energy from their living hosts, whether they are animals or plants, and are eventually killed or destroyed (Prasad et al., 2021).

Fungi can live and grow in a wide range of habitats. They can grow on a variety of surfaces, including rocks, and can be found in both terrestrial and marine environments (Mouchacca, 1995). Fungi can affect humans in both good and bad ways. They are problematic because they contaminate food, wood, fabrics, cereals, seeds, and many other manufactured or stored things. They induce serious plant diseases, so, they are bad for agriculture. Last but not least, they result in superficial and deep mycotic infections, which are harmful to both humans and animals (Gupta et al., 2018; Kour et al., 2019).

Fungi are common in both the natural world and as commensals in humans. Through inhalation, ingesting, and physical contact, humans are frequently exposed to a wide range of fungi that are present in the environment (Hamon and Quintin, 2016). For instance, there are more than 50 genera of commensal fungi, but the most common ones on the skin are Malassezia Baill, Aspergillus P. Micheli, and Penicillium Link., whereas the most common ones in the gut are Candida Berkhout., Saccharomyces Meyen., and Cladosporium Link. (Iliev et al., 2012; Hoffman et al., 2013). To maintain a strong defence against fungal infections, the immune system must be functioning properly. When this barrier is broken, invasive and superficial fungal infections lead to diseases that can result in abrasive and potentially fatal issues (Plato et al., 2015; Wheeler et al., 2016).

The most prevalent fungal disorders, which affect approximately 25% of the global population, are those affecting the skin and nails (Havlickova et al., 2008). According to Hünniger and Kurzai (2019), acquired as well as congenital impairments of innate and adaptive immune responses are the main causes of invasive fungal infections in immuno-compromised individuals. Although invasive fungal infections are less common than superficial infections, they are more dangerous due to their high morbidity and fatality rates (Brown et al., 2012). Only a few hundred of the estimated 1.5–5 million fungal species (O'Brien et al., 2005) are known to cause diseases among humans (Köhler et al., 2014).

Pneumocystis P. Delanoë & Delanoë., Aspergillus P. Micheli., Candida Berkhout., and Cryptococcus Kütz. species are responsible for more than 80% of human deaths (Brown et al., 2012; Khaushik et al., 2015). Although most of these fungi are harmless and even make up a portion of the human microbiome, if they spread throughout the body, they can result in illnesses that are lethal (Strickland and Shi, 2021).

Animals and fungi have coevolved; the complex and potent human immune system was created in response to the on-going risk posed by the microbial world. In contrast to plants, insects, and ectothermic vertebrates, mammals are highly resistant to invasive fungal infections, and also the evolution of endothermy and homeothermy have enhanced immunity against fungi in mammals (Robert and Casadevall, 2009; Bergman and Casadevall, 2010).

Fungi may attempt to form a mutualistic association with humans but this association is hampered by their heterotrophic and absorptive mode of nutrition and the intrinsic resistance of white blood cells to penetrate any foreign invader. The impact of fungi on humans has been highlighted in this review, and as a result, it has been demonstrated that professional phagocytes, in particular monocytes, macrophages, dendritic cells, and poly-morphonuclear neutrophilic granulocytes, have been shown to be crucial for triggering and regulating antifungal immune responses, eliminating fungal pathogens and not forming a mutualistic relationship with fungi.

Mode of nutrition in fungi and humans

Like fungi, humans are unable to prepare their own food. Food is obtained from other resources. Both humans and fungi are heterotrophs with an absorptive mode of nutrition. Unlike fungi, which digest food externally and then directly absorb nutrients via its cell wall, humans digest food internally before absorbing the nutrients and also the difference lies in the circulation of nutrients through blood in humans.

The true fungi acquire their carbon components from saprophytes, which are non-living organic substrates, or parasites, which are living organic materials, by nutrient absorption through their cell wall. Small molecules simply diffuse through the cell wall after accumulating in a watery film that surrounds the hyphae (such as simple sugars and amino acids). On the other hand, macromolecules and insoluble polymers (such as proteins, glycogen, starch, and cellulose) need to go through preliminary digestion in order to be absorbed by the fungal cell. Specific proteolytic, glycolytic, or lipolytic enzymes are released from the hyphae during this process, the substrate(s) are broken down extracellularly, and the digestive end products are diffused through the fungal cell envelope. These digestive enzymes let fungal pathogens to penetrate the natural host barriers. The glucose present in human blood is the source of carbon for the fungus. However, leukocytes prevent fungus from utilizing the carbon in human blood (Melnikova et al., 1997; Biedermann and Vega, 2020).

Criteria for a fungus to invade a human

A fungus must be heat resistant, able to move through or across host defences, able to lyse and absorb carbon from human cells, and able to survive host immunity in order to invade humans.

Casadevall and his colleagues claim that the development of endothermy and homeothermy resulted in the creation of a "thermal exclusionary zone" where the growth of fungus is constrained by warmer hosts. Thus, the fungus must be able to resist the host's body temperature in order to invade (Robert and Casadevall, 2009).

The second requirement for a fungus to invade a person is the ability to move within the human body. For a fungus to remain at a suitable location, adhesion molecules are virulence factors connected to fungal mobility methods (Oliveira et al., 2015). Another crucial virulence factor associated with fungal movement is morphogenesis. Hyphal morphogenesis helps in protection of fungi from phagocyte ingestion and killing (Neilson et al., 1978).

The third requirement for a fungus to utilise the host as a nutrient substrate is the secretion of digestive enzymes suitable to breakdown and absrorption of carbon from human cells. Only fungi that secrete hydrolases appropriate for digesting human cells can invade people, including primary human invaders like Histoplasma capsulatum Darling . as well as opportunistic intruders like Fusarium spp. Link. or Aspergillus fumigatus Fresen . (Barata et al., 2002; Kogan et al., 2004).

The evolution of immunity and phagocytosis is a fundamental human ability to eradicate any outside invader (Davies et al., 1991).

Disease Mechanism of Fungi

Entry

Numerous entry points allow fungi to enter the body. Malassezia furfur (C.P. Robin) Baill. is common in areas of the skin where there are many sebaceous glands. Only in a few peculiar situations it causes infection. Exogenous fungi also cause diseases in humans. When fungi unintentionally breach defences like intact skin and mucous membrane linings, are these circumstances conducive to fungal colonisation and proliferation.

Adaptation and Propagation

In order to more easily propagate within the host, many fungi have developed strategies. For instance, dermatophytes that reside on skin, hair, and nails secrete enzymes that break down keratin. Histoplasma capsulatum Darling., Blastomyces dermatitidis Gilchrist & W.R. Stokes., and Paracoccidioides brasiliensis (Splend.) F.P. Almeida. are three examples of systemic fungi that are moulds in nature but change into unicellular organisms when they begin to cause disease. When Candida albicans (C.P. Robin) Berkhout. invades tissues, it transforms from its commensal yeast-like morphology into a filamentous form. The ability of different Candida Berkhout. species to adhere to host tissues and the production of capsules by Cryptococcus neoformans (San Felice) Vuill. are the two further features that affect their pathogenicity.

Dissemination

The majority of the times, disseminated fungal infections are a sign of compromised host defences. Such a breach is the result of the endocrinopathies and immunological disorders (Finlay and Falkow, 1989; Okeke and Muller, 1991; Maresca et al., 1994).

Spectrum of mycoses

Numerous diseases in humans are brought on by fungal infections, or mycoses. Mycoses come in a variety of degrees of severity, from simple skin infections that damage the stratum corneum to severe conditions that impact the kidneys, liver, brain, heart, and other vital organs.

Primary mycoses versus opportunistic mycoses

The primary fungal species can infect a healthy host; in contrast, opportunistic fungus needs a vulnerable host to spread infection. Most often, the respiratory tract is the route by which the primary fungal species enter the host. Fungi that cause deep mycosis are opportunistic and can enter the body through the digestive system, the respiratory system, or intravascular devices.

Blastomyces dermatitidis Gilchrist & W.R. Stokes., Histoplasma capsulatum Darling., Paracoccidioides brasiliensis (Splend.) F.P. Almeida. and Coccidioides immitis C.W. Stiles. are the primary systemic fungal species. Numerous Candida Berkhout., Aspergillus P. Micheli., Penicillium Link., Trichosporon Phaff, M.W. Mill. & Shifrine. and Fusarium Link . species are among the opportunistic fungal species. Most human fungal species are classified based on the tissues or organs they first colonise (Walsh et al., 1995). They are discussed below:

Superficial Fungal Infections

A superficial fungal infection only affects the epidermis' outermost stratum corneum layers or the hair shaft's cuticle.The host's immune system rarely reacts to these illnesses. Through indwelling catheters or intravenous lines, patients unintentionally contract these common fungal invaders.

Dermatophyte Infections

 Dermatophytes colonise the skin, hair, and nails of the living host. These fungi are more pervasive than those that cause superficial infections, but they are only present in keratinized tissues. From a trivial infection to a systemic, extremely inflammatory one, they have the capacity to induce a wide variety of diseases. When skin is wounded or macerated, these fungi enter through the integument and cornified layers of skin, where they settle down and produce keratinase to break down the fibrous and insoluble keratin protein.

Subcutaneous infections

Fungi that have been linked to subcutaneous mycoses are abundant in the environment and are not highly infectious. These organisms are traumatically inserted into the subcutaneous tissues. Because the wounded tissue has a lower redox potential, histopathologic evidence implies that these organisms exist in the subcutaneous tissue layers by creating proteolytic enzymes and maintaining facultative microaerophilic conditions.

Systemic infections

For systemic mycoses, the respiratory system is the main site of infection. Inhaled conidia and other infectious particles fall to the mucosal membrane of the respiratory tract or the alveoli, where they come into contact with macrophages and are phagocytosed. These organisms need to be able to tolerate the high body temperature, avoid being eaten by phagocytic cells, defeat any opposition they come across, or adapt in a way that will allow them to replicate in order to successfully colonise the host (Rotrosen et al., 1986; Walsh and Pizzo, 1988; Odds et al., 1992).

Composition of blood in humans

 The vital bodily fluid known as blood is responsible for many physiological activities. A unit volume of human blood contains approximately 50% plasma, 40–45% red blood cells (RBCs, also called erythrocytes), and a negligibly small amount of white blood cells (WBCs, also called leucocytes) and platelets.

Plasma

A combination of proteins, salts, sugar and fat make the fluid portion of blood known as plasma. It contains chemical messengers like hormones, clotting proteins and antibodies. While the primary function of plasma is to carry blood cells throughout the body.

Red Blood Cells (also called erythrocytes or RBCs)

Red blood cells make up around 40 to 45% of the volume of blood and are the most numerous cells in the body. A special protein called haemoglobin is present in red blood cells and aids in the movement of oxygen from the lungs to the body's tissues as well as the return of carbon dioxide from the body for expiration (Basu and Kulkarni, 2014; Atkins et al., 2017).

White Blood Cells (also called leukocytes or WBCs)

White blood cells defend the immune system of the human body. Compared to red blood cells, they are far less common, making up just around 1% of the blood.

Types of White Blood Cells

There are two main groups of leukocytes in the blood- Granulocytes and A granulocytes.

Granulocytes

These leukocytes are characterized by the presence of granules in their cytoplasm. These granulated cells include eosinophils, basophils and neutrophils.

Eosinophils

Small granulocytes called eosinophils comprise about 2 to 3% of all WBCs and are formed in the bone marrow. The digestive system contains significant numbers of these cells. These cells help in controlling mechanisms related to allergies and asthma.

Basophils

They make up between 0.5 and 1% of WBCs, making them the least common granulocyte. They have enormous cytoplasmic granules that, by releasing histamine and causing blood vessel dilation, are crucial in the development of a non-specific immune response to pathogens and allergic reactions.

Neutrophils

They account for 60 to 65% of WBCs. Neutrophils aid in the killing of germs via lysosomes and functions as a powerful oxidant. Neutrophils are also the first immune system cells to respond to any foreign invasion by micro-organisms.

Agranulocytes

These leukocytes do not have granules in their cytoplasm. These agranulated cells include monocytes and lymphocytes.

Monocytes

 They account for 6 to 10% of WBCs. The three main functions of monocytes are to migrate into tissues and remove dead cells, to protect against bloodborne pathogens, and to quickly reach infection sites in tissues.

Lymphocytes

The other major category of white blood cells is lymphocytes. They are crucial for the body's defence and are commonly referred to as natural killer cells. T lymphocytes and B lymphocytes are the two main subgroups of lymphocytes. T lymphocytes work to control the activity of other immune cells as well as to directly attack certain tumours cells. Antibodies are proteins made by B lymphocytes that specifically target bacteria, viruses, and any other foreign invader (Ziegler, 2000; Gautam and Bhadauria, 2018).

Platelets (also called thrombocytes)

 Megakaryocytes are very large cells that are broken down into tiny pieces to form platelets, also known as thrombocytes. By concentrating at the site of an injury, sticking to the lining of the damaged blood artery, and creating a foundation for blood coagulation, platelets help the blood clotting process (also known as coagulation) (Hartenstein, 2006).

Interaction of fungi with human blood

The interaction between host and fungus is crucial for an outcome. Most of the fungi have commensal (symbiotic) interaction with the host and immune system creates tolerance between host and the commensal fungi. If the relationship between host and guest remain balanced then it may be converted into mutualism. If the balance between the host immune system and fungus is disrupted, the fungus will become more opportunistic and turned into parasite or pathogen and then this interaction becomes an infection (Del and Casadevall, 2012; Cassone and Cauda, 2012).

The fungus that infects healthy people devotes a significant percentage of its physiology to evading or combating the immune system (Robert and Casadevall, 2009; Bergman and Casadevall, 2010; Garcia and Casadevall, 2010). The earliest and most fundamental immune response to outside invaders including bacteria, viruses, fungi, etc. is referred to as innate immunity. As part of an innate immune response, the skin, mucosal epithelial surfaces of the mouth, gastrointestinal tract, and genitourinary tract function as the body's first line of defence. The mucosa's and skin's surface both produce antimicrobial substances. If the fungus penetrates these physical barriers, the innate immune responses will be triggered (Hardison et al., 2012; Leopold and Wormley, 2015).

Neutrophils and macrophages in particular serve as sentinels for the identification and eradication of fungal invasions in the innate immune system (Erwig and Gow, 2016). The typical list of human professional phagocytes includes macrophages, monocytes, and polymorphonuclear neutrophilic granulocytes (neutrophils). Later, it was discovered that dendritic cells, particularly in their young condition, serve as effective phagocytes (Zaragoza and Nielson, 2013; Gilbert et al., 2015).

Polymorphonuclear neutrophils (PMNs) are the most frequent leukocytes necessary for the start of an inflammatory response to a fungal infection. Neutrophils, the primary effector or phagocytic cells of the innate immune system, are the most numerous PMNs (Traynor and Huffnagle, 2001). Neutrophil granulocytes, which are important phagocytic cells that are brought in early to the infection site, activate a wide range of antimicrobial mechanisms, including phagocytosis, the release of granule enzymes and anti-microbial peptides, and the formation of neutrophil extracellular traps (NETs) (Urban et al., 2006; Robinson, 2009; Nordenfelt and Tapper, 2011).

Neutrophils can also stop the growth of fungi by depriving them of essential nutrients (Urban et al., 2009). The importance of neutrophils is shown by the finding that people with neutropenia or those who have impaired neutrophil function are especially vulnerable to systemic fungi infections (Lehrer and Cline, 1969; Martino et al., 1989; Diamond, 1993; Cheng et al., 2012).

Up to 10% of the leukocytes in human blood are monocytes. These cells circulate in the bloodstream for several days before diffusing into tissue and developing into macrophages and dendritic cells. Phagocytosis, antigen presentation, and immune activation or modulation through cytokine synthesis, are the three primary tasks of monocytes, macrophages and dendritic cells of the immune system (Auffray et al., 2009).

The blood's monocytes are constantly traversing cells and non-sterile interfaces on the surfaces of epithelia, where they develop into macrophages. Macrophages live longer than neutrophils and use chemotaxis to hunt their microbial prey. Studies have demonstrated the role of macrophages in combating fungal infection by revealing that how a decrease in mononuclear phagocytes results in faster fungal proliferation in tissues and increased mortality. As a result, understanding the outcome of host-phagocyte interactions also demands the understanding of the immunological condition of the host (Qian et al., 1994; Romani et al., 1997).

When macrophages engulf the fungus, a series of events begins, including phagosome-lysosome fusion, the generation of reactive oxygen intermediates (ROI), and reactive nitrogen intermediates. Additionally, by producing the cytokines and chemokines that attract and activate extra immune cells to the infection site, tissue-resident macrophages perform a crucial function as effector cells.

 The initial responses brought on by macrophages help in the elimination of the infection and restrict its spread. Macrophages that have been activated will polarise and differentiate into M1 (traditional activated macrophages) and M2 (alternative activated macrophages). By supplying microbicidal and pro-inflammatory components, M1 macrophages promote fungal clearance, whereas M2 macrophages are involved in the persistence of fungus inside the macrophages and produce an anti-inflammatory response (Gordon and Martinez, 2010; Martinez et al., 2009; Reales-Calderón et al., 2014).

Despite being less effective in eliminating pathogens, Dendritic cells are crucial for processing and presenting antigen to T lymphocytes (Netea et al., 2004). After identifying the fungus, DC cells will prepare the antigens for presentation to naive T cells in the draining lymph nodes. This causes the T-cell commitment linage to be directed toward T-helper (Th) subsets such Th1, Th2, and Th17 cells. These Th profile subgroups are crucial for protective immune responses against fungal invasion (Borghi et al., 2014; Zelante et al., 2015).

Mutualistic interaction of gut bacteria in human body as an example

The skin, saliva, oral mucosa, conjunctiva, and gastrointestinal tract, interior and external surfaces of the human body are inhabited by a very large number of bacteria that have coevolved with humans (Sender et al., 2016; Thursby and Juge, 2017). The colon, which contains an estimated ~10 ¹⁴ bacteria, is where the great majority of commensal bacteria are found, followed by the skin, which has an estimated ~10 ¹² bacteria (Savage, 1977).

The rest of the body has fewer than 10 ¹² of bacterial population (Tannock, 1999; Berg, 1996). They are referred to as the "microbiota" or "microbiome" collectively (Berg et al., 2020). The bacterial phyla Firmicutes and Bacteroidetes make up more than 90% of the bacterial cells in a healthy adult intestine (Tlaskalová et al., 2004; Schippa and Conte, 2014).

On the levels of the endocrine system, the nervous system, the immune system, and the metabolism, the gut microbiota and the host are intertwined in a mutualistic connection (Bäckhed et al., 2004). The host's intestine benefits the most from the gut microbiota because it ensures that gut functionality in terms of digestion, energy absorption, mucosal immunity, intestinal barrier integrity, defence against pathogens, production of vitamins, neurotransmitters (NT), and potentially bioactive substances, such as short-chain fatty acids (SCFAs), which are beneficial molecules for the host, is at its best.

The gut and its accompanying bacteria could be referred to as a "microbial-assisted digestive system" because of the intimate relationship between the gut and gut-microbiota. To put it another way, the bacteria in the human gut seem to have a considerable buffering role in food digestion (Tremaroli and B€ackhed, 2012; Paone and Cani, 2020).

The gut microbiota is referred to as a community of cells capable of cooperating in many metabolic reactions necessary for the biotransformation of foreign molecules that humans cannot easily metabolise, such as drugs, xenobiotics, polyphenols, antibiotics, and chemical food additives. In addition to being a catabolic system as previously mentioned for its additional and complementary role in digestion, the gut microbiota is also referred to as a system that is capable of catabolism.

Knowing that there are only 57 cytochrome P450 enzymes in humans and around 3000 cytochrome P450 enzymes in gut bacteria suffices to grasp the metabolic significance of the gut microbiota. The human gut microbiota is now widely believed to be significant for health (Wahlstr€om et al., 2016; Van et al., 2018; Lindsay et al., 2020). In response to all these benefits for their host, these bacteria only absorb fibres (indigestible complex carbohydrate for humans) from human gut through their enzymatic activity (Donaldson et al., 2016).

Conclusion

Today, one of the most challenging diseases to treat in people is fungal infections. We have emphasised in this review that there may be commensal relationship between fungi and humans; can they never be mutualistic ones? The human body contains fungi, which are always considered as disease-causing organisms. The majority of fungal infections affect those people with impaired immune systems. Natural selection has given white blood cells and innate immune cells the capacity to combat and exterminate invaders as the body's first line of defence. Therefore, it becomes impossible for humans and fungi to associate in a mutualistic way. Given the prevalence of deadly fungal infections and the deaths they cause, it is imperative to put much more effort into knowing how the immune system functions at its best to combat fungi. Although common for bacterial species, the idea of mutualistic relationship between fungi and the human host is a new concept as the potential benefit to the host of harbouring fungi is still unknown.

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