Mechanism Of Bacterial Infections And The Difficulty In Eradicating Them Globally

Infectious Diseases and Their Impact

Infectious disease arising out of bacteria can be transmitted from animals to people and from one person to another person. These infections can be mild to severe and can eventually lead to the development of serious illness that if left out may lead to life threatening diseases (Nelson and Williams 2013). According to the reports published by the Parliamentary Office of Science and Technology in UK (2017), infectious diseases cause significant economic and health burden in UK which accounts to about 7% of death and with an annual cost of £30bn. However, even under the presence of broad spectrum and third or fourth generation antibiotics and presence of advanced quality molecular detection technology, the overall eradication of the microbial diseases in UK and both globally is not very promising. The following essay is mainly based on argument that why there is a difficulty in eradicating the infections and life threatening diseases from UK or rather says globally.  In doing so, the essay will mainly explore the mechanism of bacterial adherence and colonization within the host cell via the use of cell adhesion molecule, fimbriae or Pilli. The essay also aims to throw light on the effects of bacterial toxins in disease propagation and difficulty in prevention. In order to critically analyse the opinion and come to a conclusion, the essay will also discuss the importance of antibiotics and is relation to disease prevention and subsequent generation of multi-drug resistance gene (MDR) along with the overall concept of biofilm production and its barrier towards antibiotics. The essay will also discuss the role of microflora and its effect on immune-compromised people and roots behind spread of infection. At the end essay will try to recommend the possible ways that are showing promising results in the eradication of the bacterial infections.

The capability of the bacteria to cause disease reflects the relative pathogenicity. Virulence is the measure of the pathogenicity of the virus. The degree of the virulence is linked to the ability of the organism for causing diseases in spite of the host resistance mechanism of the body. The factors that are produced by the microorganism and disease are called the virulence factors, such as the toxins and the surface coats that inhibit the phagocytosis and the surface receptors binding to the host cells.

In order to cause infection, the bacteria should adhere to the mucosal surface. For example, the mucosa of the alimentary tract is repeatedly cleaned by the mucus secreted by the goblet cells and by the peristaltic movement of the gut content over the epithelium. In order to establish infection in such a site, the bacteria have to adhere to the mucosal surface. For accomplishing this, bacteria have evolved certain mechanism such as fimbriae that recognize and help in attachment of the bacteria (Haiko and Westerlund-Wikström 2013). The colonization factors of the bacteria play an important role in the pathogenic mechanism of the bacteria.

Mechanism of Bacterial Adherence and Colonization

The external surface of bacteria acts as the central interface between the pathogen and the host and recognition of the exposed surface by the immune system provided by the host a key sign for the microbial clearance (Haiko and Westerlund-Wikström 2013). A study by Olsen et al. (2013) have shown that the flagellum of a bacteria influences the virulence by facilitating movement. There are early studies that have shown that the single polar flagellum of Vibrio cholera is crucial for its virulence. Again V. Cholera that is not motile cannot induced virulence. Recently, Olsen and colleagues have proved the involvement of the serovar specific differences of the chemotaxis genes and flagella in the adhesion of the Salmonella.  It also provides the pathogen to mimic the immune modulators of the host, in order to modify the immune responses of the host or to express receptor ligands or adhesions for anchoring to the host surfaces (Haiko and Westerlund-Wikström 2013). Supporting this findings, Girón and colleagues that some of the wild type strains of E. Coli expressing the H2 or H6 flagella can adhere and form micro-colonies to the HeLa cells.  

 Other surface molecules like the protective capsules can increase the survival of the pathogen within the host (Willey et al. 2008). A common mechanism to mask the complex antigenic surface from spotting by the immune surveillance is the expression of a carbohydrate capsule. For example Streptococcus pneumonia, uses its capsule to prevent the deposition of the complement and antibody on its surface, thereby preventing clearance by phagocytosis or opsonisation (Finlay and McFadden 2006). The lipid A component of the Lipopolysaccharide (LPS), present in the Gram negative bacteria, plays a crucial role in the activation of the TLR. However the outer part of the LPS consists of variable forms of carbohydrates providing each of the strain with their unique serotype (O antigen). Thus different strains can infect the same host due to different surface antigens (Finlay and McFadden 2006). There are certain gram negative bacteria that alter the lipid A for altering the TLR4 response. For Example, There are two component sensors present in Salmonella; (PhoP/PhoQ) that can sense the host environment regulating many genes. Modification of the lipid A makes it much less active for TLR4 activation (Prescott and Harley 1994).

The bacterial pathogens have developed special secretion system for exporting the virulence factors across the bacterial membranes. Virulence factors such as the toxins or the immune modulators are secreted in to the host cells. Both the type III secretion systems (T3SS) and type IV secretion systems (T4SS), can introduce, various virulence factors in to the host cells. These two types of secretion system possess very diverse repertoire of the effector molecules that can be delivered in to the host cells, paralyzing the phagocytosis and altering other immune functions (Finlay and McFadden 2006). Although the structures of the gram positive bacteria are much simpler, they can also generate specialized pores for delivering the bacterial molecules. Furthermore antigenic variation in the bacteria is also the main reason why bacterial invasion cannot be prevented. The mechanism usually follows one of the three mechanisms 1) bearing multiple copies of the molecules, each having an independent on/off switch. 2) Possessing one expression locus with many silent copies of the gene and constant modification of the expressed genes 3) Presence of a highly variable region that keeps on changing. For example the Neisseria species contains 10-11 outer membrane Opa proteins, which are antigenically different from each other and hence can switch the terminal sugar structures.

Strategy	Bacterial example
Surface modulators –	Lipid A of LPS, capsules, adhesions, invasions (Duan et al. 2013).
Antigenic hypervariability	– pili, outer membrane proteins, LPS, variation from one strain to the other.
Killing of the immune cells/phagocytes	Super antigens, – blocking the inflammatory pathways by the injection of the effectors.
Inhibit complement	Production of capsules and long chain LPS for avoiding complement deposition and attack of MAC.
Interfere with TLRs	Alteration of the TLR ligands to lessen recognition.
Hide from immune surveillance	Avoiding phago-lysosomal fusion and inhibiting phagocytosis.

The Effects of Bacterial Toxins in Disease Propagation

Bio-films and the spread of nocosomial infection

Multidrug-resistant (MDR) organisms like Methicillin-resistant Staphylococcus aureus (MRSA), Acinetobacter baumanni and extended spectrum beta lactum producing gram-negative bacteria are frequently highlighted as the main causative agent behind the acute and chronic infectious diseases which lead to the generation of significant mortality and morbidity along with overall increase in the health care cost (McGrath and Asmar 2011). Till date various studies have indicated that the human infections are mainly caused by the ability of the bacteria to develop surface attached polymicrobial communities which are popularly known as biofilms (Sánchez et al. 2013). According to Flemming et al. (2016), microbial biofilms are made of a groups of bacterial cells which are adherent to the surface and are enclosed with in a self-produced extracellular matrix. Adaptation to the surface attached growth within a biofilm is accompanied via a significant change in the protein and gene expression along with the overall microbial activity. Numerous pathogenic and nosocomial bacteria have been observed to exist predominantly as biofilms under both natural environment and under infected tissues as polymicrobial communities. Notably, the formation of biofilms is implicated as one of the significant factors behind the increased number of the chronic bacterial infections (Sánchez et al. 2013).  

The randomised control trial (RCT) conducted by Sánchez et al. (2013) from the clinical isolated of the patients suffering from bacterial infection, highlighted that the formation of biofilms increases the tendency of recurrent bacterial infection. Their RCT showed that MDR pathogens are more prone towards the formation of biofilms and the strains from the patients with persistent bacterial infection generated positive results in biofilm formation. The systematic review conducted by Bjarnsholt (2013) showed that the biofilm infections like the pneumonia in cystic fibrosis patients, chronic otitis media, chronic wounds and other catheter or implant associated infections affects millions of people both the developed and developing countries each year and numerous death toll occurs due to this. In general, it can be said that the bacteria has two types of life forms during their growth and proliferation stage. In one life form, bacteria exist, as single cell aggregates (planktonic) whereas in other life forms, bacteria are organized into sessile aggregates. This aggregate form is commonly referred to as bioflim, which increases the rate of nocosomial infections (Bjarnsholt 2013). For example, lung infection is the principal cause of mortality and mortality among the patients of cystic fibrosis and this mostly dominated by Pseudomonas aeruginosa. The growth of biofilm makes the eradication of infection impossible and thereby leading to chronic inflammation in the airways that ultimately leads to death (Ciofu et al. 2015). In relation to this Olsen (2015) highlighted that biofilms can be difficult to eradicate when they lead to the generation of the biofilm-related diseases like the cystic fibrosis, implant infections, periodontal diseases and urinary tract infections. A number of phenotypic features associated with the biofilms leads to the generation of the biofilm-specific resistance and tolerance however, the exact molecular mechanisms involved in the process of generation of antibiotic tolerance is still not known. However, de la Fuente-Núñez et al. (2013) is of the opinion that the antibiotic resistance conferred by the biofilms to the bacterial colony is mainly due to the ability of the biofilm to survive in the hostile environment. de la Fuente-Núñez et al. (2013) stated that under the clinical settings, bacteria are exposure to several adverse condition like stress, nutrient limitations, heat shock and anaerobiosis. This adverse condition lead to the generation of adaptive responses in the bacterial cells, which in turn leads to the development of highly resistant multicellular structures that are recalcitrant to the host immune clearance system and at the same time are extremely difficult to eradicate through the administration of antibiotics.

The Role of Antibiotics and Multi-Drug Resistance Gene

Ciofu et al. (2015) is of the opinion that the weakening of the bioflims through quorum sensing inhibitors and antibiotic guided killing through pharmacokinetics and pharmacodynamics of antibiotics are frequently suggested as remedies to prevent the colonization of biofilms. In the domain of quorum sensing, O’Loughlin et al. (2013) highlighted that the quorum-sensing inhibitor blocks Pseudomonas aeruginosa virulence factor and biofilm formation. The synthetic molecule, meta-bromo-thiolactone not only prevents virulence expression of Pseudomonas but at the same time prevents biofilm formation.

In spite of having quorum sensing as an important factor behind the inhibition of the bacterial, the fast colonization and spread of infection of bacteria further increases the susceptibility of the bacterial infection. The research conducted by Los et al. (2013) highlighted that the pore-forming toxins (PFTs) are the most common virulence factor in a wide range of bacterial pathogen including Streptococcus pneumonia, Mycobacterium tuberculosis, and Escherichia coli. This PFT rapidly disrupt the host cell membrane and thereby entering into the host cell via the pore. Once inside the host cell, the toxin takes the control of the host pathways and thereby causing cellular damage and increasing the chronicity of infection.  

The fact that disease can never be irradiated can be supported by the fact that, although normal micro flora is harmless, but very few can actually cause diseases in immune-compromised host. Since a diverse community of microorganisms resides in the intestine of the human (Taur and Pamer 2013). The host intestinal tract possess a local immune system for controlling the microbial flora. This includes the gut associated dendritic cells, B-cells and T- cells and Peyer’s patches, in order to prevent the entry of the microorganisms in the tissues. The goblet cells produces the mucus that prevents the penetration of the bacteria (Steele 2012). According to Taur and Pamer (2013) patients suffer from systemic bacterial infection after being treated with cytotoxic chemotherapy.  The chemotherapic regimens for the cancer patients that are meant for inhibiting the replication of the tumour can be harmful for the elements in the bone marrow, including the white blood cells that are immune-competent. Even the patient’s keep under extraordinary support system have much greater risk of colonization with multi-resistant microorganisms. As per the evidences, the digestive tract can become portals of entry for the human pathogens even when there are no mucosal barriers. Bacterial translocation by a specialized absorptive cells known as the M cells, are the part of the antigen sampling process leading to the development of the gut associated lymphoid tissue (Johansson and Rasmussen 2013). Taur and Pamer, (2013) have postulated that after passing through the intestinal layer, the bacteria id phagocytised by the motile phagocytes, by which they are transported to the extra-intestinal sites. Facultative anaerobes like Salmonella spp. and Listeria spp. Can translocate out of the intestinal tract and this is found mainly in the patient with disrupted T-cell function or those suffering from Lymphoma, AIDS or organ transplant.

Concept of Biofilm Production and Its Barrier towards Antibiotics

The burden of the Clostridium difficile infection (CDI), has augmented in terms of morbidity, incidence, cost and mortality and is one of the commonest cause of the infections (Janoir 2016). Di Bella et al. (2015) have stated that in comparison to specific categories of immunosuppression, the HIV infected patients are likely to develop CDI in comparison to the other hospitalized patients. In a nationwide study conducted in USA, the solid organ transplant has been found to be an independent predictor of the hospital mortality, colectomy and graft complications.

Development of multidrug resistant micro-organism is another reason behind the recurrent bacterial infection. Antibiotic resistance of the bacteria is recognized as one of the principal threats to human health throughout the world. For example, MRSA kills more people worldwide in comparison to the HIV/AIDS, homicide and Parkinson’s disease. Globally, there are 3.7% of new cases of tuberculosis reported and these new strains of tuberculosis are resistant to isoniazid and rifampicin. Apart from tuberculosis, evidence also indicated the existence of carbapenem-resistant enterobacteriaceae spp. and extended beta-lactamase producing Enterobacteriacea. The main reason highlighted by the increase in the antibiotic resistance among the microbial pathogen includes high rate of consumption of antibiotics (Llor and Bjerrum 2014). According to Llor and Bjerrum (2014), there is a direct correlation between the use of antibiotics and generation of antibiotic resistance. Countries with the higher consumption of antibiotics like in European countries have higher rate of antibiotic resistance. Ventola (2015) highlighted a completely different perspective behind the increase in the antibiotic resistance. According to Ventola (2015), inappropriate prescribing of antibiotic also leads to the generation of multidrug resistance bacteria. Studies have indicated that choice of agents or duration of the antibiotic therapy leads to the development of antibiotic resistance.

Zilberberg et al. (2014) is of the opinion that the improper dosage of antibiotic leads to the change in the antibiotic induced gene expression and thereby increasing virulence. Improper use of antibiotic also leads to microbial mutagenesis and leading to the development of antibiotic resistance and subsequently rapid spread of the disease. In order to study the improper dosage of antibiotics on the generation of multidrug resistance bacteria, Zilberberg et al. (2014) conducted single-centre retrospective cohort study over the adult patients in the intensive care units who are suffering from bacteremia or severe sepsis due to gram negative bacterial infection. There results highlighted that the inappropriate use of the antibiotics or in appropriate dosage of antibiotics lead to the development of multidrug resistant (MDR) bacteria and thereby increasing the chances of hospital mortaility and re-infection by the same bacteria.

The Role of Microflora in Bacterial Infections

Extensive use of agriculture is another reason behind the increase in the generation of multidrug resistance bacteria. In the United Kingdom, antibiotics are widely used as growth supplements in animal husbandry (Gelband et al. 2015). It is also used to prevent infection. According to Rinsky et al. (2013), treating livestock with antibiotics is said to improve the overall health of the animal and thereby helping to gee rate larger yields and higher-quality of product. Anomaly (2015) is of the opinion that human ingests the antibiotics, which are used for livestock rising, when they feed them. This leads to the transfer of resistant bacteria to human body leading to the development of antibiotic resistance. The research conducted by Rinsky et al. (2013), is of the opinion that the molecular detection method demonstrated the existence of the resistant bacteria in the farm animals and this reach to the consumers when they consume the meat of that animal. This occurs through a series of steps. At first the antibiotic used in the process of food producing animals kills or suppresses susceptible bacteria and thereby enabling the antibiotic-resistant bacteria to thrive. These antibiotic resistant bacteria are transmitted through the food supply and causing infections in human that may lead to adverse health consequences (Van Boeckel et al. 2015).

In relation to the use of antibiotics in the livestock raising and its effects on human health, Seiffert et al. (2013) conducted a study. According to Seiffert et al. (2013), Salmonella spp., Escherichia coli and Acinetobacter spp. are important human pathogens causing serious infections to mankind. These infections are mainly treated via the application of extended spectrum cephalosporins (ESCs). However, during the past few decades, it has been highlighted that there is a rapid increase in the infections along with colonization of ESC-resistant isolates. The reason highlighted by Seiffert et al. (2013) is overuse of antibiotics or lack of completion of the antibiotic dosage generates resistance in the bacterial strain. This generation of resistance within the bacterial strain is mainly mediated by the formation of plasmid-mediated AmpCs or carbapenemase enzyme or via the production of extended spectrum beta lactamase gene within the bacteria. This production of the antibiotic specific lyses enzyme within the bacteria cleaves or inactivates antibiotics resulting in the spread of the infection or recurrent infection. Animals are considered as the principal reservoirs of MDR gram negative organisms due to the overuse of antibiotics in the veterinary medicines. This overuse of antibiotics in veterinary medicine has lead to the specific selection of ESC R E. coli, ESC-R Salmonella spp and to a lesser extent of MDR Acinetobacter spp. This complex scenario is responsible for the expansion of MDR organisms which have life-threatening significance over human race (Seiffert et al. 2013).

Possible Ways to Eradicate Bacterial Infections

Figure: Molecular mechanisms of antibiotic resistance

Source: (Jansen et al. 2018)

Vaccinations are the important alternatives to address antimicrobial resistance (Ginsburg and Klugman, 2017). The antibiotic resistance bacteria not only causes treatment failure but also increases the health care costs. Decreasing the development of the antibiotic resistance by the adoption of expanded vaccination has shown promising results.  For example the introduction of the pneumococcal vaccine in northern California prevented the prescription of 35 antibiotics per 100 vaccinated children. As per this finding, the scientists have suggested that pneumococcal conjugate vaccine can prevent about 1.4 millions of antibiotic prescriptions.

Vaccines work by training the immune mechanism of the body to identify and respond to the pathogen by mounting an immediate immune response against the pathogen. According to Jansen et al. (2018) there are certain ways by which the unvaccinated individuals in the population can be protected. Herd immunity is the process by which the application of vaccination to the majority of the people reduces the transmission of the diseases to those who are unvaccinated or who are immune-compromised (Mishra et al. 2013). Haemophilus influenza type b vaccines were not only effective against the invasive disease in the infants that were immunized but also significantly lessened the use of the antibiotics. Jansen et al. (2018) in the paper have also stated that the routine use of the Hib conjugated vaccines also decreased the nasopharyngeal carriage. This was mainly noticed in case of a herd vaccination.

Plague had been one of the costliest pandemic in the history of humankind resulting in the mortality of almost 75 to 200 million people in the year 1346-53. It was considered as the “black death” during the 14 ^th century (WHO. 2018). Plague outbreaks was mainly controlled by maintaining the personal hygiene, finding and stopping the source of the infection, protecting the health workers and the plague patients by a seven-day chemoprophylaxis, routine hand washing and safe burial practice lead to the eradication of the plague.

Vaccination can be an ideal choice for treating any pandemics but WHO does not recommend vaccination, except for the high-risk groups that are always exposed to the risk of transmission such as the laboratory workers and the health care workers. According to (WHO. 2018) plague has not been eradicated fully; it is endemic in Madagascar and the Democratic republic of Congo. Surprisingly it is still there in US. According to recent researches, the black footed ferrets and the Canada lynx are the susceptible species and it is the animal reservoir, which makes the eradication of the plague hard.

Conclusion

Thus from the above discussion, it can be concluded that eradicating the overall rate of occurrence of the bacterial infection is difficult in the present day scenario. One of the important reasons highlighted behind this is the capability of the bacteria in the domain rapid colonization and high pathogenicity in the adherence proteins. This diversity in the adherence protein mimics the host defence mechanism thereby leading to prompt colonization of bacterial strain and rapid of infection. Moreover, analysis of the scientific journals also lead to the elucidation that the production of the bacterial toxins help in rapid entry of the bacterial cells within the host body and thereby taking the entire control over the host cell mechanisms leading to rapid spread of the infection. However, the application of antibiotics is not significantly useful in decreasing the spread of the bacterial infection because of the increase rate of generation of MDR genes in bacteria. The main reason behind the generation of the MDR gene is over or under use of antibiotics and also the use of antibiotics in the livestock raising. Moreover, generation of the adverse bacterial environment within the host cell arising out of the antibiotics leads to the generation of bio films which makes the entry of antibiotic within the bacterial cell even more difficult making the bacterial culture more susceptible for the nosocomial infection. Not only the external or pathogenic bacteria, but the micro flora residing within the host body also increases the infection threat among the individuals and the condition is more prominent among the immune-compromised individuals or individuals made immune-compromised artificially like those suffering from cancer or have undergone organ transplantation. This immune-compromised state leads to the generation of the immune response leading to the generation of hypersensitivity. Moreover, this immune-compromised state also makes an individual to susceptible more towards the microbial infections leading to the overall cure or eradication of the bacterial colonization difficult. However, analysis of few studies on bio film lead to the elucidation that of concept of quorum sensing which help to eradicate the harmful effect of biofilm and thereby helping to decrease the susceptibility of bacterial infection.

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