“With reference to specific examples, discuss how knowledge of microbial virulence strategies and/or host-pathogen interactions can enable the identification of novel strategies for the prevention and/or treatment of infectious diseases’’
Although the prevention and treatment of infectious diseases has improved over the last decades due to the widespread use of vaccines and anti-infectives and the development of infection control measurements, bacterial infections are still a major cause of morbidity and mortality worldwide. (Andre, et al., 2008). In particular, global spreading of antibiotic resistance genes and their acquisition by clinically relevant bacterial pathogens constitute a serious public health problem. Resistance of important pathogens to standard antimicrobial therapies and the emergence of multidrug-resistant bacteria, also referred to as superbugs (Zaman, et al., 2017), have become one our greatest challenges in the combat of bacterial infections and accompanied disease (Akova, 2016). A report published by the Centre for Disease Control and Prevention (CDC) in 2013 estimates that more than 2 million infections and 23,000 deaths are caused by antibiotic-resistant bacteria in the USA annually (Anon., 2013). The lack of successful prevention measures, shortage of effective drugs and only a small number of new antibiotics in the clinical pipeline demand the innovation of novel strategies, and alternative antimicrobial therapies to treat and prevent infectious diseases (Hughes & Karlén, 2014).
N. meningitidis is a Gram-negative bacteria, hosted exclusively by men. It is an opportunistic pathogen, colonizing the upper respiratory tract, without causing damage to the host. In susceptible individuals the bacterium can cross the epithelial layer into the bloodstream, causing septicemia and/or meningitis. The different N. meningitidis strains are divided in 12 serogroups, one being MenB. Every year 500,000 cases of septicaemia and meningitis worldwide are caused by MenB (Kuhdari, et al., 2016). For many years, it has been attempted to develop a vaccine against MenB, but no satisfying results were obtained because it’s capsule is a self-antigen (Hill, et al., 2010). The design of protein-based meningococcal vaccines is complicated by the important level of genetic and antigenic diversity expressed by the meningococcus (Bai & Borrow, 2010). To give broad protection against MenB, a vaccine must consider a high level of antigenic variability (O’ryan, et al., 2013). One novel strategy employed to formulate a vaccine for serogroup B is called ‘reverse vaccinology’ technique which was used by Rappuoli et al. (2001). The technique used applies bioinformatic tools to comprehensively screen pathogens’ genome data for surface-expressed proteins, in order to select candidate vaccine antigens. Proteins likely to be used as vaccine antigens are identified and further tested for immunogenicity on animal models. This technique was able to identify several proteins in MenB including factor H binding protein (fHbp). fHbp is an important virulence factor expressed by N. meningitidis to evade innate immune defences by specifically binding to complement factor H (fH), a down-regulator of the complement alternative pathway (Luo, et al., 2016). A study by Seib, et al. (2009) showed the effect of knocking out fHbp from MenB in an ex vivo human whole blood model of meningococcal septicaemia. This demonstrated that all fHBP knockout mutant strains were highly sensitive to killing by both human whole blood and human serum compared to their wild-type parent strains (1 to 2 log10 less survival for fHBP knockout strains than for the wild type strains). These results indicate that bacterial killing in serum is mediated by complement. This is consistent with the role of fHBP in providing resistance to complement-mediated killing. Presently, fHbp forms part of multiple licensed MenB vaccines. Bexsero® is a licensed vaccine that has been shown to be approximately 80% effective against currently circulating stains of MenB (Biagini, et al., 2016).
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Urinary tract infections (UTIs) are one of the most common pathological conditions in both community and hospital settings. It has been estimated that about 150 million people worldwide develop a Urinary Tract Infection (UTI) each year, with high social costs in terms of medical expenses (Terlizzi, et al., 2017). Among the common uropathogens associated to UTIs development, UroPathogenic Escherichia coli (UPEC) is the main culprit. UTIs are routinely treated with antibiotic therapy. Women experiencing at least two UTIs per year are frequently given antibiotics prophylactically (Beerepoot, et al., 2011). Unsurprisingly, the rates of resistance to antibiotics in UPEC strains have shown a steady increase over the past few decades (Mike, et al., 2016). There are no currently licensed vaccines in the United States to combat recurrent UTIs in women. Licensed vaccines in Europe have been shown to be ineffective, and therefore, haven’t been licensed for use in the United States (Tammen, 1990). Recently, studies have been performed in an attempt to produce a new UPEC vaccine by targeting the bacteria’s ability to acquire iron (Mike, et al., 2016). Iron is an essential cofactor in many biological processes, including DNA synthesis, electron transfer, and central metabolism (Skaar & Raffatellu, 2015). The mammalian host limits intracellular and freely circulating iron by sequestering iron in proteins such as lactoferrin, transferrin, ferritin, and haemoglobin (Miethke & Marahiel, 2007). Since iron is not readily available, microorganisms produce small high affinity chelating molecules called siderophores for its acquisition (Saha, et al., 2013). In addition, the primary site of UPEC infection, the bladder, has even lower iron levels than the rest of the body. Thus over 14 gene clusters implicated in iron acquisition have been identified as important virulence factors in UPEC strains (Subashchandrabose & Mobley, 2015). These gene clusters encode up to four siderophore biosynthesis and uptake systems. A study by Mike, et al. (2016) explains that E. coli strains typically encode a combination of stealth siderophores, which are not recognized by host defences. Studies have also systematically assessed the use of surface-exposed iron receptors as potential vaccine antigens and found that two of the stealth siderophore receptors, those that recognize Ybt and Aer siderophores, protect against UTI (Alteri, et al., 2009, Brumbaugh, et al., 2013). This information provides a new platform for the synthesis of novel vaccines for UTI. It also serves as an example of how knowledge of microbial virulence strategies can enable the identification of novel methods for the prevention of infectious diseases.
Bacteria are continously at war against multiple competitors and thus require weapons to conquer new territory or persist in an ecological niche. One important weapon is the Type 6 Secretion System (T6SS). The T6SSs of Gram-negative bacteria are effector translocation apparatuses, resembling an inverted bacteriophage-puncturing device, capable of antibacterial activity (Gallique, et al., 2017). Until recently, it was thought that the T6SS was only able to kill other bacterial cells. Since bacteria exist in the environment amongst different microorganisms, not only bacteria, it would make sense that bacteria had tools to interact and compete with these other microorganisms too. A study by Trunk et al. (2018) showed that the ‘antibacterial’ T6SS of Serratia marcescens can act against fungal cells, including pathogenic Candida species. Cellular proteomics combined with genetic analysis led them to discover the first T6SS-dependent antifungal effectors, Tfe1 and Tfe2. The two effectors elicit distinct responses in fungal cells and can exert a fungicidal effect. The study highlights that the deployment of T6SSs enabling simultaneous attack on prokaryotic and fungal rivals should represent a key determinant of bacterial competitive fitness in polymicrobial human infections. None of the existing systemic antifungals satisfy the medical need completely (Georgopapadakou, et al., 1998). The ability of T6SSs to directly deliver potent antimicrobials to bacterial and fungal pathogens makes the system an attractive candidate for the engineering of novel antimicrobial, including antifungal, mechanisms into probiotic organisms. Such an antimicrobial approach would benefit from the capacity of T6SS to function in a biofilm, which is a growth state that is notoriously difficult to treat owing to its increased resistance to traditional antimicrobial (Russell, et al., 2014).
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Our increasing understanding of bacterial virulence strategies and the induced molecular pathways of the infectious disease provides novel opportunities to target and interfere with crucial pathogenicity factors or virulence-associated traits of the bacteria while bypassing the evolutionary pressure on the bacterium to develop resistance. This targeted intervention effectively disarms the pathogen and enables its clearance by the host immune system, whilst delaying the emergence of resistance (Mühlen & Dersch, 2015). Upon entering the host, bacterial pathogens such as UPEC must travel to their respective site of infection in order to initialize the disease process. Once the bacteria reach the site of infection, bacterial cell surface structures and appendages such as pili detect and interact tightly with specific host cell receptors to adhere to the host cell (Mühlen & Dersch, 2015). Cell attachment enables bacteria to withstand host mechanical and immunological clearance and is crucial for the initiation of an infection, whilst gaining access to the host tissue (Thanassi, et al., 2012). Agents targeting bacterial adherence would not only deny access to host tissues, but would also promote rapid clearance of the bacteria and avoid the translocation of tissue-damaging effectors. These agents could make novel antimicrobials. Bicyclic 2-pyridones and N-substituted amino acid derivatives were discovered as potential pilicides that target conserved regions on the chaperone and competitively inhibit the binding of the chaperone to the pilin subunits (Pinkner, et al., 2006). In UPEC, they were shown to inhibit biogenesis of type 1 and P pili, the major cause of urinary tract infections, which decrease UPEC binding to bladder cells by 90 %. While none of the substances affect bacterial growth, pilicides may have broad-spectrum activity as both the chaperone structure and the chaperone– usher pathway are highly conserved among bacteria, and make them excellent candidates as an antimicrobial.
The present review takes a close look at current strategies to prevent and treat infectious diseases. The review also illustrates the promising advances made in our attempts to develop alternatives to antibiotic therapies and overcome the current antibiotic crisis. To fully exploit these strategies, it is imperative that we improve our understanding of the molecular mechanisms and the consequences of host–pathogen interactions, as many crucial virulence-associated processes remain unclear.
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