Molecular determinants of peaceful coexistence versus invasiveness of non-Typhoidal Salmonella: Implications in long-term side-effects
Introduction
Salmonella, Gram-negative, rod shaped, facultative anaerobe and enteric pathogen which belongs to the family bacteriaceae, was first isolated and discovered in the porcine intestine in the year 1885 by Theobald Smith and was named after his colleague who worked with him, Dr. Daniel E. Salmon (Smith, 1894.; Su and Chiu, 2007). Salmonella infection is either host specific or includes multiple hosts depending upon the species and serotypes. Within the genus Salmonella, more than 2500 serovars exist and are known to cause infections in multiple hosts including humans, poultry and cattle (Tanner and Kingsley, 2018). In a broader sense, Salmonella is classified into human restricted typhoid causing serovars (eg. S. Typhi and S. Paratyphi) and wide host range non typhoidal serovars (NTS) such as S. Typhimurium and S. Entritidis. The main source of Salmonella infection in humans is contaminated food or water, however indirect contact through droppings and water from aquariums where infected reptiles, amphibians live also pose a risk for salmonellosis. In humans, ailments caused by Salmonella range from gastroenteritis, a localised intestinal infection to a systemic enteric fever called typhoid or enteric fever. Infection with S. Typhi and S. Paratyphi results in typhoid, while that with NTS serovars result in a localized gut inflammation referred as gastroenteritis. Together, the typhoidal strains and NTS possess a huge global burden in terms of mortality and morbidity. Among these, the NTS strains have higher incidence of infectivity, with about 95 million cases of enterocolitis reported in the year 2017 (Roth et al., 2018). NTS mediated gastroenteritis is a self-limiting infection lasting for no more than 5–7 days, nonetheless in rare cases, such as immunocompromised and malnourished patients, these infections can lead to chronic infections and systemic spread. Around 0.15% and 3.9% of overall infections in adults and in children respectively can contribute to chronic state. Chronic carriage lead to recurrent intestinal infections and thus shedding of bacteria in faecal matter, which can thereof enter into the environment, hence becoming source of outbreaks (Gunn et al., 2014). Chronic states can also lead to bacteremia and sepsis in susceptible genetic background resulting in increased morbidity and mortality. The prevalence of Salmonella as the most frequently isolated pathogen from hospitalized patients suffering from bacteremia in Africa and Asia was recently established by a systematic review and meta-analysis study (reviewed in Marchello et al., 2019). The emergence of invasive NTS strains (iNTS) over the last 30–40 years, have further aggravated the situation. Among 5,35,000 cases of iNTS reported in the year 2017, ~78000 contributed to death indicating association of huge mortality rate with iNTS (Stanaway et al., 2019). A clear understanding of the mechanisms of systemic spread as well as chronic states of the typhoidal strains of Salmonella exist, however that of NTS is less well explored.
Salmonella has evolved and adapted to become host restricted via multiple horizontal gene transfer (HGT) events over longer time scales of several years resulting in typhoid causing strains of Salmonella. The invasive strains of NTS have emerged over short time scales resulting from point mutations, SNPs and genome degradation events (Fig. 1). Further, these invasive NTS strains have acquired multiple drug resistance cassettes in its virulence plasmids which make associated infections difficult to contain. They are adept at causing a more febrile disease by circumventing the host gut immune system and thus residing for longer duration in the host in specific niches such as reticulo-endothelial system and gallbladder (Ilyas et al., 2017; Tanner and Kingsley, 2018).
Chronic Salmonella infection is either mediated by concerted efforts of bacterial effector proteins encoded by its genome or host genetic and geographical surrounding which contribute to bacterial persistence. The effector proteins are critically important for bacterial entry, its intracellular survival and modulation of host cellular processes (Srikanth et al., 2011). In addition, these proteins also help the bacterium to circumvent the host innate and adaptive immune system and reside predominantly within macrophages (reviewed in Bernal-Bayard and Ramos-Morales, 2018; Monack et al., 2004). Salmonella reprograms the macrophages from microbicidal M1 subtype to a more tolerable niche of M2 subtype specifically by means of its Salmonella pathogenicity island II encoded effectors (Stapels et al., 2018). This allows the bacterium to not only reside for long duration but also to disseminate further to other permissible niches such as gallbladder and liver via the reticulo-endothelial system. Salmonella can persist for long durations, up to two years or more, in gallbladder as a consequence of biofilm formation and eventually trigger severe outcomes such as chronic inflammation and even cancerous transformation (Gunn et al., 2014; Scanu et al., 2015). In addition, emergence of antimicrobial resistant strains in response to extensive use of antimicrobial therapy have contributed to bacterial persistence (reviewed in Bakkeren et al., 2020).
Following the resolution of disease, in case of chronic state, patients fail to fully clear the infection and they progress to a state of long term carriage. These chronic infections not only contribute to above mentioned recurrent infections and bacteremia but can also lead to other deleterious and debilitating diseases in susceptible hosts. Chronic Salmonella infections have been associated with several unusual outcomes like reactive arthritis (ReA) (Thomson et al., 1995), inflammatory bowel disease (IBD) (Schultz et al., 2017), gallbladder cancer (GBC) (Iyer et al., 2016) and colorectal cancer (CRC) (Lu et al., 2017). Even though association studies between Salmonella infection and these diseases are predominant, studies emphasizing on the molecular mechanistic details of how these diseases are acquired upon persistent infection are very limited. Salmonella mediated molecular mechanisms and disease pathophysiology has been extensively studied, yet there is limited mechanistic information about the new invasive NTS (iNTS) strains and how persistent infections which is responsible for its transmission is achieved.
This review will provide a holistic overview about the NTS and iNTS serotypes, their origin, evolution and associated clinical manifestations. The review will dwell on the available literature elucidating how NTS mediated gastroenteritis is established and can lead to chronic infections. We will also discuss how iNTS mediated disease pathogenesis and chronicity differs from that of NTS according to the available limited studies. Further, the review will entail in understanding the different mechanisms employed by Salmonella to survive inside the host for longer duration and how these could contribute to associated chronic sequelae.
Section snippets
Evolution of invasive strains of non typhoidal Salmonella
The genus Salmonella is divided taxonomically into 2 major species- S. bongori and S. enterica. Clonal divergence of Salmonella from its common ancestor by means of multiple horizontal gene transfer (HGT) events leading to acquisition of gene loci referred to as Salmonella pathogenicity island (SPIs), have resulted in the development of thousands of serovars having diverse hosts ranging from reptiles to humans. These SPIs confer new phenotype to the recipient bacteria, thus allowing adaptation
Molecular mechanisms of localized Salmonella infections
Salmonella enterica serovar Typhimurium (hereafter S. Typhimurium or Salmonella) are responsible for diseases that range from gastroenteritis to systemic infection. Gastroenteritis caused by Salmonella infection in immunocompetent individuals remain localised to terminal ileum, colon and the mesenteric lymph nodes (MLNs) (Zhang et al., 2003). Diarrhoea, vomiting, abdominal cramps and fever are the usual symptoms of gastroenteritis caused by Salmonella. Infections are caused due to ingestion of
Determinants of invasive Non-Typhoidal Salmonella
Enteric infections with iNTS isolates in immunocompromised individuals and in young children, particularly those from the Sub-Saharan African region, are capable of causing a deadly invasive disease. Unlike enteric fever which occurs in immunocompetent individuals, iNTS disease occurs in immunocompromised adults particularly those suffering from HIV or malaria. In children, iNTS is associated with comorbidities such as malaria, malnutrition and HIV. Most cases of iNTS disease from the African
Determinants of persistent infections
If infection is not cleared, Salmonella will colonise within the host in favourable niches. Such colonization, in case of NTS, may be transient or carried for prolonged period (>1 year). Long term colonization by Salmonella in its host is referred as “persistence”. In this state the pathogen adopts a low metabolic state which may also be due to selective pressure of host immune resistance. In such persistent state if the pathogen cause damage to the host, the condition may lead to a diseased
Long term sequelae of S. Typhimurium
Existence of chronic Salmonella carriage has been recognized due to numerous epidemiological investigations over the last century. The most famous of these have been the case of Typhoid Mary in the US, the first subject of asymptomatic carriage of the bacterium. The long term persistence of Salmonella as discussed above is achieved via means of its modulation of numerous host cellular responses so as to provide the bacterium with a safe haven in host lymphoid organs and hepatobiliary system.
Future directions
NTS and iNTS isolates pose a serious health challenge to humans and animals. Recent emergence of drug resistant variants, persister phenotype, causality with other pathological conditions such as gallbladder carcinoma (GBC), inflammatory bowel disease (IBD), reactive arthritis (RA), and colon cancer (CC) adds enough reasons to invest efforts to prevent, diagnose and treat NTS related diseases. Effective vaccines against S. Typhi exists and has been administered to millions of people
Conclusions
The genus Salmonella has evolved from a non-pathogenic ancestor, by multiple genome alteration events propelled by horizontal gene transfer (HGT), spontaneous mutations and acquisition of plasmids. These evolutionary events have given rise to emergence of notorious pathovars with increased capacities to infect and cause diseases of different manifestations in a range of hosts. Unlike the typhoidal strains, which cause an enteric fever in humans and are host restricted, the non-typhoidal strains
Acknowledgements
Work in our laboratory is supported by: RCB core grant, Scheme for Transformational and Advanced Research in Science ministry of Human Resources Development Grant (STARS MHRD), and Science and Engineering Board Grant of Department of Science and Technology (SERB-DST). All figures in this article were created using BioRender.
References (232)
- et al.
The Acid Tolerance Response of Salmonella spp.: An adaptive strategy to survive in stressful environments prevailing in foods and the host
Food Res. Int.
(2012) - et al.
The phosphoinositide phosphatase SopB manipulates membrane surface charge and trafficking of the salmonella-containing vacuole
Cell Host Microbe
(2010) - et al.
The Salmonella effector SteD mediates MARCH8-dependent ubiquitination of MHC II molecules and inhibits T cell activation
Cell Host Microbe
(2016) - et al.
Pseudogenization of the secreted effector gene sseI confers rapid systemic dissemination of S. Typhimurium ST313 within migratory dendritic cells
Cell Host Microbe
(2017) - et al.
A Salmonella toxin promotes persister formation through acetylation of tRNA
Mol. Cell.
(2016) - et al.
Characterization of O-antigen delivered by generalized modules for membrane antigens (GMMA) vaccine candidates against nontyphoidal Salmonella
Vaccine
(2017) - et al.
Salmonella require the fatty acid regulator PPARδ for the establishment of a metabolic environment essential for long-term persistence
Cell Host Microbe
(2013) - et al.
Invasive non-typhoidal salmonella disease: an emerging and neglected tropical disease in Africa
Lancet
(2012) - et al.
SopE and SopE2 from Salmonella typhimurium activate different sets of RhoGTPases of the host cell
J. Biol. Chem.
(2001) - et al.
Oxygen requirement for the biosynthesis of theS-2-hydroxymyristate moiety in Salmonella typhimurium lipid A: FUNCTION OF LpxO, A new Fe2+/α-KETOGLUTARATE-DEPENDENT dioxygenase homologue*
J. Biol. Chem.
(2000)
Life-threatening bacteraemia in HIV-1 seropositive adults admitted to hospital in Nairobi, Kenya
Lancet
Clinical presentation of non-typhoidal Salmonella bacteraemia in Malawian children
Trans. R. Soc. Trop. Med. Hyg.
Salmonella lipopolysaccharide in synovial cells from patients with reactive arthritis
Lancet
Salmonella chronic carriage: epidemiology, diagnosis, and gallbladder persistence
Trends Microbiol.
Activation of a RhoA/myosin II-dependent but arp2/3 complex-independent pathway facilitates Salmonella invasion
Cell Host Microbe
Tartaric acid metabolism. I. Subunits OF L(+)-TARTARIC acid DEHYDRASE
J. Biol. Chem.
Salmonella activation of STAT3 signaling by SarA effector promotes intracellular replication and production of IL-10
Cell Rep.
Toll-like receptors and their crosstalk with other innate receptors in infection and immunity
Immunity
Enteric pathogens and reactive arthritis: a systematic review of Campylobacter, Salmonella and shigella-associated reactive arthritis
J. Health Popul. Nutr.
Salmonella typhimurium coordinately regulates FliC location and reduces dendritic cell activation and antigen presentation to CD4+ T cells
J. Immunol.
NLRP6 negatively regulates innate immunity and host defence against bacterial pathogens
Nature
Salmonella exploits HLA-B27 and host unfolded protein responses to promote intracellular replication
Ann. Rheum. Dis.
Global burden of invasive nontyphoidal Salmonella disease, 2010(1)
Emerg. Infect. Dis.
Invasive Salmonella exploits divergent immune evasion strategies in infected and bystander dendritic cell subsets
Nat. Commun.
Evolutionary causes and consequences of bacterial antibiotic persistence
Nat. Rev. Microbiol.
Identification of SopE2, a Salmonella secreted protein which is highly homologous to SopE and involved in bacterial invasion of epithelial cells
J. Bacteriol.
Pretreatment of mice with streptomycin provides a Salmonella enterica serovar Typhimurium colitis model that allows analysis of both pathogen and host
Infect. Immun.
A low pH-inducible, PhoPQ-dependent acid tolerance response protects Salmonella typhimurium against inorganic acid stress
J. Bacteriol.
Molecular mechanisms used by Salmonella to evade the immune system
Curr. Issues Mol. Biol.
Salmonella enterica serovar typhimurium travels to mesenteric lymph nodes both with host cells and autonomously
J. Immunol.
Salmonella Typhimurium effector SseI inhibits chemotaxis and increases host cell survival by deamidation of heterotrimeric Gi proteins
PLoS Pathog.
Characterization of Salmonella-induced filaments (Sifs) reveals a delayed interaction between Salmonella-containing vacuoles and late endocytic compartments
Traffic
Adding function to the genome of African Salmonella Typhimurium ST313 strain D23580
PLoS Biol.
Non-typhoidal Salmonella Typhimurium ST313 isolates that cause bacteremia in humans stimulate less inflammasome activation than ST19 isolates associated with gastroenteritis
Pathogens and Disease
Chlamydia pneumoniae infection and risk for lung cancer
Cancer Epidemiol. Biomark. Prev.
Recombinant Salmonella typhimurium outer membrane protein A is recognized by synovial fluid CD8 cells and stimulates synovial fluid mononuclear cells to produce interleukin (IL)-17/IL-23 in patients with reactive arthritis and undifferentiated spondyloarthropathy
Clin. Exp. Immunol.
Cutting edge: Salmonella AvrA effector inhibits the key proinflammatory, anti-apoptotic NF-κB pathway
J. Immunol.
Regulatory protein HilD stimulates Salmonella Typhimurium invasiveness by promoting smooth swimming via the methyl-accepting chemotaxis protein McpC
Nat. Commun.
Gallstones play a significant role in Salmonella spp. gallbladder colonization and carriage
PNAS
Horizontally acquired glycosyltransferase operons drive salmonellae lipopolysaccharide diversity
PLoS Genet.
Salmonella Prosthetic Joint Septic Arthritis 4
The typhoid toxin promotes host survival and the establishment of a persistent asymptomatic infection
PLoS Pathog.
The mechanism of Salmonella entry determines the vacuolar environment and intracellular gene expression
Traffic
Salmonella trafficking is defined by continuous dynamic interactions with the endolysosomal system
Traffic
Gallbladder carriage generates genetic variation and genome degradation in Salmonella Typhi
PLoS Pathog.
Identification of altered genes in gallbladder cancer as potential driver mutations for diagnostic and prognostic purposes: a computational approach
Canc. Inf.
Susceptibility to Salmonella typhimurium infection and effectiveness of vaccination in mice deficient in the tumor necrosis factor Alpha p55 receptor
Infect. Immun.
Drug resistance in Salmonella enterica ser. Typhimurium bloodstream infection, Malawi
Emerg. Infect. Dis.
Three epidemics of invasive multidrug-resistant Salmonella bloodstream infection in blantyre, Malawi, 1998-2014
Clin. Infect. Dis.
The intestinal microbiota plays a role in Salmonella-induced colitis independent of pathogen colonization
PloS One
Cited by (3)
Enterobacteriaceae: Salmonella
2022, Veterinary Microbiology: Fourth EditionSome peculiarities of the molecular pathogenesis of gastroenteritis caused by non-typhoidal Salmonella
2022, Eksperimental'naya i Klinicheskaya Gastroenterologiya/Experimental and Clinical Gastroenterology
- 1
Equal contribution.