Keywords

1.1 Introduction

Infection is defined as multiplication or colonization of microorganisms on the host system or invading into the host cells. Despite the presence of substantial number of bacteria in the human body, their occurrence in healthy persons is usually limited to some body parts like the skin, vagina, the mucosae of nasal and buccal cavities and, most significantly, the gastrointestinal part (Schommer and Gallo 2013; Costello et al. 2009; Lemon et al. 2010). However, opportunistic pathogens colonize on the host cells for prolonged period and they cause diseases occasionally. Among the microorganisms, most deadly microorganism is virus which has the ability to hijack the host system to replicate themselves. It is very difficult to diagnose as well as to eradicate the viral diseases completely. Fungi deploy different cell associated virulence factors or secrete virulence factors to modify the host cell completely. Vector borne microbial infection is another global problem. Here we will summarize some human microbial diseases and their virulence factors.

1.1.1 Colonization of Host Surfaces by Pathogenic Microorganisms

Roughly 300–400 m2 of surface area are represented by respiratory, digestive, and urogenital mucosae (200 times more than that of the skin) and hence these sites make maximum contact with bacteria. These sites consist of three layers: an epithelium, a loose connective tissue layered lamina propria, and the thin layered smooth muscles. These mucosal surfaces constitute frontline barriers and hence limit the invasion by both pathogenic and commensal bacteria. These sites are not suitable for colonization of the pathogens. Ciliary movement has been observed of the epithelial cells that aid to clear the pathogens from the host system. Various molecular strategies have been deployed by pathogenic bacteria for adherence to these epithelia and to proliferate at their surface by circumventing the high defense barriers.

1.1.2 Initiation and Maintenance of Pathogens in Intracellular Lifestyle

Bacterial pathogens have diverse advantages by maintaining intracellular lifestyle, i.e., they are not attacked by humoral and complement-mediated immune system; a broad range of nutrients are accessible to them and they avoid shear stress-induced clearance. However, these intracellular bacteria are targeted by different mechanisms employed by the host cells. Thus, intracellular pathogens have evolved different strategies to successfully establish and maintain an intracellular infection for a prolonged period.

1.1.3 Crossing of Host Barriers by Pathogens

Diverse types of sentinel cells like dendritic cells (DCs) and M cells continuously sense the existence of pathogenic bacteria rich mucosal environment. Though there is coordination between innate and adaptive immune response to utmost the colonization of pathogens in the host, sometimes pathogens use as entry portals. Specialized cells such as M cells are found in the intestinal epithelium and other epithelia in humans. M cells transport antigens from the lumen to cells of the immune system. Thus, they initiate an immune response or tolerance. Their function is different from that of their adjacent epithelial cells. Antigens of the mucosal environment are recognized by DCs and play a middle role in the adaptive immunity. Mucosal tissues are enriched with these cells but sometimes these cells may migrate to mesenteric lymph nodes, where they interconnect with lymphocytes.

1.2 Microbial Infections

1.2.1 Bacterial Infections

Staphylococcus aureus is a classic opportunistic pathogen which causes skin and soft tissue infection (SSTI) worldwide. Various infections are caused by them, ranging from self-limiting skin infections to extreme life-threatening pneumonia, bacteremia, and endocarditis (Moran et al. 2006; David and Daum 2010; Talan et al. 2011). There are several microorganisms which cause skin infection. Life-threatening condition with high mortality happens when bacteria infect the central nervous system (CNS). Additionally, it may cause permanent neurological deficits in survivors (Geyer et al. 2019). Sometimes, some diseases are caused by two different genera of microorganisms like cystic fibrosis (CF). CF lung is first colonized by S. aureus, but in the adulthood stage, Pseudomonas aeruginosa acts as the second colonizer, the most common isolated bacterium causing chronic lung infections (LiPuma 2010). More specifically, methicillin-resistant S. aureus (MRSA) is an infamous cause of healthcare-associated and community-associated disease along with Acinetobacter baumannii, with an estimated prevalence of about 30%. They colonize in chronic obstructive lung disease (COPD) affected hospitalized patients (Furuno et al. 2008; David and Daum 2010).

Bacterial meningitis, another deadly disease in sub-Saharan Africa, is caused by both Neisseria meningitides and Streptococcus pneumoniae. S. pneumoniae, the second most common pathogen, causes higher morbidity and mortality than N. meningitides in the same region (Ramakrishnan et al. 2009; Gessner et al. 2010; Mihret et al. 2016). Haemophilus influenzae also contributes to 2% of meningitides (Mihret et al. 2016). Brucellosis, a zoonotic disease, in humans the disease is identified by recurrent undulant fever, endocarditis, debilitating arthritis, and meningitis (Corbel 1997; Godfroid et al. 2011). It causes considerable economic loss and becomes a major public health burden (Pappas et al. 2005; Pappas 2010). Keratitis, a common form of corneal blindness across the globe, is caused by both bacteria and fungi. P. aeruginosa, an opportunistic human pathogen, causes chronic pulmonary infections in cystic fibrosis (CF) patients (Winstanley and Fothergill 2009). P. aeruginosa also affects immune-compromised individuals having human immunodeficiency virus (HIV) or undergoing cancer chemotherapy and those with burn wounds (Lau et al. 2004).

Clostridia, strict anaerobic bacteria, have been isolated from necrotizing infections in humans (Zhao-Fleming et al. 2017). In recent times, several bacterial species especially Clostridia like Clostridium butyricum, C. perfringens, and C. neonatale have been associated with necrotizing enterocolitis (NEC) outbreaks (Hosny et al. 2017; Roze et al. 2017). Life-threatening diseases in humans and animals are caused by pathogens, carried by well-known house fly. More than 100 pathogens including bacteria, viruses, fungi, and parasites (protozoans and metazoans) have been connected with the insect (Tsagaan et al. 2015; Nassiri et al. 2015). S. pneumoniae (Pneumococcus) is a gram-positive, α-hemolytic, and facultative anaerobic organism which inhabits the nasopharynx. Upper or lower meningitis, respiratory infections, and septicemia are caused by S. pneumoniae. S. pneumoniae operates major diseases with a considerably high mortality (Manco et al. 2006). Yersinia pestis causes another deadly disease, plague. It was the causative agent of epidemics in Europe during the first and second pandemics, including the Black Death, infamous for their widespread mortality and lasting social and economic impact (Bramanti et al. 2019). A life-threatening disease called Rocky Mountain spotted fever is caused by Rickettsia rickettsii, an obligately intracellular bacterium. Ticks spread this disease to human beings (Dantas-Torres 2007). Gas gangrene or clostridial myonecrosis is caused by C. perfringens type A. This disease causes rapid spread of tissue necrosis combined with a lack of leukocyte infiltration at the site of infection (Rood 1998). A chronic infectious disease called leprosy or Hansen’s disease is caused by Mycobacterium leprae. However, it was discovered that M. lepromatosis caused diffuse lepromatous leprosy (DLL) in human (Han et al. 2008; Scollard 2016). A potentially deadly disease tularemia in mammals including humans is caused by the intracellular pathogen Francisella tularensis (Tärnvik 1989). Psittacosis, an animal vector-borne disease, is caused by Chlamydia psittaci. Transmission of this fatal disease can happen to humans coming in close association with a variety of birds, most frequently Psittacidae (parrots, lories, parakeets, and cockatoos) or Columbiformes (pigeons). Exposure to equine placental material as a risk factor for transmission of Psittacosis has also been discovered recently (Polkinghorne and Greub 2017). Lyme borreliosis (LB), a tick-borne disease, is also endemic and causes serious public health problems in USA and Europe (Rosenberg 2018; Sprong et al. 2018). LB is caused by the genus Borrelia, a spirochete. Persistent infections both in the vertebrate host and tick vector are established by these pathogens (Rego et al. 2019).

1.2.2 Fungal Infections

Not only bacteria but also fungi are similarly efficient to produce several diseases in human system. Filamentous fungi such as Aspergillus fumigatus and the Scedosporium apiospermum species complex (16–58% and 9–10% respectively), the most common pathogens, are isolated from cystic fibrosis (CF) patients (Noni et al. 2017; Reece et al. 2017). Scedosporium boydii, S. apiospermum, and S. aurantiacum are frequently involved with CF patients whereas S. ellipsoidium and S. minutisporum are periodically involved with CF patients, suffering from CF lung infections with a geographically variable prevalence (Blyth et al. 2010; Zouhair et al. 2013; Sedlacek et al. 2015). Human lung mycetoma, caused by uncommon CF pathogen S. Angustum, is a previously reported disease (Kravitz et al. 2011). Fusarium spp. causes from mild superficial infections to invasive systemic infections. Localized diseases such as onychomycosis and keratitis are also caused by Fusarium spp. in normal hosts. Invasive fusariosis affected the lungs, sinuses, and visceral organs and necrotic skin lesions and positive blood cultures are developed in 60% of individuals with immune-compromised conditions (Nelson et al. 1994; Nucci et al. 2003; Lionakis and Kontoyiannis 2004). Not only healthy individual, sometimes immuno-compromised individual may also be affected. Aspergillus, most ubiquitous in nature, infects immune-compromised host and causes invasive aspergillosis which is limited to lungs (Steinbach et al. 2012; Camargo and Husain 2014; Husain et al. 2017).

1.2.3 Viral Infections

Viruses are the most crucial human pathogens among all others microorganisms. Recently, Zika virus infection has been highlighted. Upon Zika virus infection, flu-like symptoms appear; mild infection with joint pain, low to moderate fever, headache, fatigue, and rash (Posen et al. 2016; Kindhauser et al. 2016; Shuaib et al. 2016). Another deadly virus is human cytomegalovirus (HCMV) which causes a chronic infection with lifelong latency in humans. HCMV, an opportunistic pathogen, causes infection in immunosuppressed individuals causing birth defects (Mocarski et al. 2007). Japanese encephalitis (JE) causes uncontrolled inflammatory disease to the central nervous system. Neurotropic flavivirus, JE virus (JEV) cause Japanese encephalitis (JE) (Misra and Kalita 2010). Transmission of JEV occurs by mosquito vector. JEV transmits in a zoonotic cycle where pig acts as an amplifier and water bird acts as reservoir hosts (Solomon 2004). Dengue is another example of mosquito-borne disease and a global public health problem. Approximately 390 millions are affected annually due to dengue infections (Bhatt et al. 2013) (Fig. 1.1). Dengue virus DENV infections occur from asymptomatic cases to life-threatening hypovolemic shock (WHO 2009). Some viral diseases resolve within 2–6 weeks like hepatitis in humans. However, the hepatitis can become chronic in pregnant women and in immune-compromised individuals (Purcell and Emerson 2008; Aggarwal and Jameel 2011; Pérez-Gracia et al. 2017). Hepatitis E virus is transmitted with the consumption of meat, liver, sausages, and offal products derived from domestic pig, deer, and wild boar (Tei et al. 2004; Colson et al. 2010, 2012). The bite of infected mosquitoes can sometimes be dangerous as it transmits yellow fever virus (YFV), a member of the Flavivirus genus, to susceptible hosts like humans or non-human primates. Main availability of YFB is in endemic parts of Africa and South America, including Brazil (Barrett and Monath 2003). Rift valley fever is caused by Rift Valley fever virus (RVFV) in ruminants as well in humans (Bird et al. 2009). The large enveloped DNA virus poxvirus family infects a wide variety of hosts. Poxvirus outbreaks are caused by zoonotic infections of cowpox virus, monkeypox 70 virus, and recently discovered poxvirus species (Di Giulio and Eckburg 2004; Vora et al. 2015). Tick-borne encephalitis is the most occured viral disease in the Central Europe. It is one of the most famous arthropod borne diseases. The TBE virus (TBEV) belongs to the genus Flavivirus (family Flaviviridae). It consists of three different subtypes: (a) the European subtype, transmitted mainly by Ixodes ricinus, (b) the Siberian subtype, and (c) the Far Eastern subtype, which are mainly transmitted by I. persulcatus (Süss 2011). Tick and their vertebrate hosts spread the TBE virus, within particular geographical area (Dobler et al. 2011).

Fig. 1.1
figure 1

Global evidence consensus, risk, and burden of dengue in 2010 (Bhatt et al. 2013). (Reprinted with permission [License number: 4595801418447])

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1.3 Virulence Factors Associated with Microbial Infections

Virulence factors are produced by pathogenic microorganisms to promote diseases (Table 1.1). These factors are either protein or carbohydrate or lipid in nature. Virulence factors are either secreted or cell mediated or cytosolic in nature and they can interfere the immune system of host cells. The cytosolic factors aid the bacterium to undertake quick adaptive—physiological, metabolic, and morphological shifts for the survival within host cells. The bacterium adheres and evades the host cell by the membrane-associated virulence factors. The secretory factors help the bacterium to avoid the innate and adaptive immune response mounted within the host. The host cells are killed by the synergistic effect of secretory virulence factors of extracellular pathogens. Sometimes, they intoxicate food items by secreting toxins into them and upon injecting this contaminated food item, human will be diseased. Virulence property of an organism enables to infect the host cell and causes a disease.

Table 1.1 Microbial virulence factors involved in bacterial pathogen dissemination through mammalian host
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1.3.1 Extracellular Virulence Factors

Many pathogenic microorganisms secrete extracellular proteases and cell wall degrading enzymes, toxins that perform as important virulence factors. They are either encoded by plasmid or chromosome. Moreover, conditions like pH, bile, bicarbonate, mucus, alkalinity, and high osmolarity alter the expression of virulence factors in the gastrointestinal tract due to modulation of virulence factors of some enteropathogenic pathogenic strains by different host factors (Hofmann 1999; Begley et al. 2005; Chiang 2013). Two main virulence factors like the cytotoxin-associated gene A and the vacuolating cytotoxin A are present in gram-negative Helicobacter pylori (Fig. 1.2).

Fig. 1.2
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Pathogenic virulence factors of H. pylori and their functions. CagA cytotoxin-associated gene A, T4SS type IV secretion system, VacA vacuolating cytotoxin, LPS lipopolysaccharide (Kim 2016). (Reprinted with permission [License number: 4593700407377])

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An increased risk of developing gastric cancer is caused by these virulence factors. Thus, they regulate their virulence property to the most conducive niche of infection. E. coli (STEC) causes food-borne disease worldwide by producing Shiga toxin. Pathogenic STEC or enterohemorrhagic E. coli (EHEC) causes intestinal disorders including watery or bloody diarrhea. These disorders may ultimately develop to life-threatening diseases such as thrombotic thrombocytopenic purpura or hemolytic uremic syndrome (HUS). Keystone pathogen Porphyromonas gingivalis causes periodontal dysbiosis (Hajishengallis 2014). It processes several virulence factors that act as immunogenic molecules. P. gingivalis produces most important protease, termed as Gingipains (cysteine proteases) (Guo et al. 2010). Heme acquisition is one of the main functions of the gingipains protease (Smalley and Olczak 2017). Elastase, rhamnolipids, alginate, and lipopolysaccharide (LPS) of Pseudomonas facilitate acute Pseudomonas infection into a chronic infection (Bjarnsholt et al. 2010; Girard and Bloemberg 2008).

Clathrin-coated vesicle trafficking is modulated by Chlamydial trachomatis CT229. It controls the trafficking of both transferrin and the mannose-6-phosphate receptor for proper development. CT229 regulates several host vesicular trafficking pathways, essential for chlamydial infection (Faris et al. 2019). Adherence is another crucial virulence factor for most of the pathogens. Adhesin-deficient S. aureus was eliminated rapidly and it suggested adherence played crucial function for maintaining colonization process (Mulcahy et al. 2012; Weidenmaier et al. 2004). C. trachomatis and L. monocytogenes secrete the second messenger cyclic dimeric (c-di)-AMP that binds straight to stimulator of interferon (IFN) genes (STING) (Woodward et al. 2010; Barker et al. 2013), whereas STING is activated by several other pathogens in a cyclic GMP–AMP synthase (cGAS)-dependent manner (Zhang et al. 2014; Watson et al. 2015). However, Brucella abortus functions differently. STING directly detects bacterial cyclic dinucleotides (CDNs) and hence response of type I IFN is triggered. This leads to the upregulation of several IFN-related genes, including guanylate-binding proteins (GBPs) (Costa Franco et al. 2018).

Majority of S. aureus isolates secrete alpha-hemolysin (Hla), a toxin which forms pore (Li et al. 2009). Hla hijacks the host molecule ADAM10, a disintegrin and metalloprotease 10, and disrupts cell junctions. Thus it infects invariably (Kennedy et al. 2010; Inoshima et al. 2012; Malachowa et al. 2013). Neuraminidase, produced by S. Pneumoniae, cleaves sialic acid from cell surface glycans and mucin. It exposes host cell surface receptors and thus it promotes S. Pneumoniae to colonize on the upper respiratory tract (Kelly et al. 1967; O’Toole et al. 1971; Paton et al. 1993). Toxin is another secreted virulence factor that facilitates pathogenic microorganisms to invade the immune system. Bacillus anthracis, a gram-positive endospore forming android shaped bacteria, causes Anthrax. B. anthracis carries two extrachromosomal plasmids, namely pXO1 and pXO2. Plasmid pXO1 encodes protective antigen, edema factor, lethal factor, and anthrax toxin activator A (AtxA). All these toxins act as a central regulator for toxin synthesis (Hammerstrom et al. 2011). These secreted toxins require a short duration of time to establish a systemic infection. Moreover, the capsule synthesizing proteins are encoded by plasmid pXO2. Disruption occurs on the membrane integrity of host cells due to pore forming anthrolysin O, another crucial virulence factor (Shannon et al. 2003). S. dysgalactiae secretes hyaluronidase whose molecular weight is approximately 55 kDa. However, the value of this protein has not been determined (Sting et al. 1990). S. zooepidemicus produces a lytic enzyme called zoocin A (zooA). The cell walls of some closely related streptococcal species are specifically targeted by zooA. The sequence of zooA was determined by cloning it (Simmonds et al. 1997). Group B Streptococcus strains produce 12 kDa molecular weight novel pyrogenic toxin which causes streptococcal toxic shock-like syndrome (TSLS) (Schlievert et al. 1993). C. perfringens type A produces the most toxic extracellular enzyme alpha-toxin which is strictly required for its pathogenicity (Awad et al. 1995; Ellemor et al. 1999). Alpha-toxin hydrolyzes both major constituents of eukaryotic cell membranes phosphatidylcholine and sphingomyelin due to its phospholipase activity (Rood 1998; Titball and Rood 2000). Enterotoxin, produced by S. aureus, causes several diseases and food-borne diseases are one of them. Staphylococcal food-borne diseases are the most occurred (Archer and Young 1988; Bean et al. 1990; Bunning et al. 1997). Botulism toxin is a neurotoxin and causes severe food-borne illness. Another neurotoxin is tetanus toxin which consists of a heavy chain and light chain. Light chain translocates to the cytosol by binding neuroselectively followed by internalization and intraneuronal sorting. Light chain cleaved at a single site of Synaptobrevin and SNAP-25 with unique selectivity and thus synaptic transmission is catalytically inhibited (Poulain et al. 1988; Bittner et al. 1989; Mochida et al. 1990; Kurazono et al. 1992; Niemann et al. 1994). Neurotoxin complex of C. botulinum type A consists of a core neurotoxin protein, several toxin-associated hemagglutinin (HA) proteins, and a non-toxin non-hemagglutinin (NTNH) protein. The continuous advancement in the knowledge of the botulinum toxin’s molecular mechanism has aided to proceed parallel in their clinical use (Cordivari et al. 2004; Grumelli et al. 2005).

All of these above discussed toxins are exotoxins. Gram negative bacteria contain another type of toxin and this has been called endotoxin as it is cell associated and not secreted out of the cells (Table 1.2). Lipopolysaccharide (LPS) acts as an endotoxin secreted from gram-negative microorganisms. LPS is made of three parts: core polysaccharide, lipid A, and O antigen. Among these, O antigen is the most variable part and as a result, antibody could not recognize O antigen. Nowadays, LPS is well-known as a crucial factor responsible for toxic indication of severe gram-negative infections and generalized inflammation (Alving 1993). Both types of toxins have many differences (Table 1.2).

Table 1.2 Major differences between exotoxin and endotoxin
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1.3.2 Cell Associated Virulence Factors

Capsule is a classic example among cell associated virulence factors. The capsule of B. anthracis consists of poly-γ-d-glutamic acid. It blocks the phagocytosis of B. anthracis during infection and hence it is weakly immunogenic in nature (Makino et al. 2002). Host cell phagocytic receptors and/or specific pattern recognition receptors (PRRs) recognize various cell surface ligands of mycobacteria like HSP70, phosphatidylinositol mannoside (PIM), 19 kDa lipoarabinomannan (LAM), and lipoprotein (Dorhoi et al. 2011). However, uptake by some of the receptors is advantageous for the pathogen’s survival. Another encapsulated bacteria is Streptococcus which causes some serious invasive infections, including septicemia, pneumonia, and meningitis. They contain capsular material which contains sialic acid and it acts as a virulence factor (Jacques et al. 1990).

1.4 Conclusion

Microbial infection is one of the serious problems worldwide and it needs to be focused. More than half of the human death occurs annually due to microbial infections. Poor hygiene, overuse of antibiotics, and lack of education are the main reasons for microbial infection. However, very few pathogens have been discovered till date. Microbes deploy several novel strategies to attack host cells and sometimes it is very hard or almost impossible task to treat these microbial diseases. Microbes cause infections by secreting various virulence factors that manipulate the host cell system. It can be either secreted or cell associated. Sometimes, they cause disease indirectly like in case of food-borne illness where microbes secrete toxins into the food and the humans are infected with those toxin-contaminated foods. Further studies on the pathogenic microorganisms aid to discover more novel pathways and virulence factors that harm human host cells.