A Review of Poultry Product as a Source of Spreading Multidrug Resistant Salmonella: Public Health Importance

In the last few decades, foodborne disease has become one of the world's health problems with various pathogenic bacteria that accompanies the contamination of food products of animal origin. One of the foodborne diseases that is always reported every year is related to Salmonella contamination in poultry products which can cause Salmonellosis in humans. Salmonella contamination become important not because of its virulence ability to invade humans, but also because of its increased resistance to various clinical antimicrobial classes, with various cellular genetic elements that can be spread in humans along the food chain. The purpose of this review is to provide an overview of the role of poultry product in the spread of multidrug resistance Salmonella which may have implications for public health. Keyword: Foodborne Disease; Salmonella; Virulence Factor; Multidrug-Resistance; Mobile Genetic Element


INTRODUCTION
Foodborne disease has become one of the global public health problems lately, given its implications for health and the economy. Various kinds of pathogens play a role in foodborne disease (Ejoet al., 2016). It is estimated that 17.9% of all foodborne diseases related to poultry and 19% of foodborne diseases associated with poultry are caused by Salmonella enterica contamination and infection O'Bryan et al., 2022).Foodborne disease caused by Salmonella infection, distributed in animals and foodstuffs of animal origin (Pires and Hald, 2010) and considered as the main carrier for humans (Ejo et al, 2016). In various parts of the world, foodborne disease caused by Salmonellosis, causes an increase in invasive disease, hospitalization and death (Pires and Hald, 2010) which can have a significant effect on children, the elderly and immunocompromised (Ding and Fu, 2016). Globally, there are 94 million cases of gastroenteritis and 155,000 deaths caused by Salmonella infection each year (Yang et all, 2019).
Salmonella contamination occurs through consumption of contaminated food such as eggs, milk and poultry meat. Twenty percent of the world's poultry products are contaminated with Salmonella and the bacteria can persist for a long time in the environment, animal facilities and through biofilm formation. In most outbreaks of Salmonellosis due to consumption of poultry products, it is known that S. Enteritidis and S. Typhimurium are the most isolated serovar (Afshari et all, 2018). Infections caused by Non-Typhoid Salmonella (NTS), particularly S. Enteritidis andS. Typhimuriumare the most commonly reported infections associated with Salmonellosis in humans (Yang et all, 2019). S. Enteritidis andS. Typhimuriumare pathogenic because of their ability to invade, replicate and survive in human host cells (Sodagari et al, 2020). The pathogenesis of Salmonella and its interaction with the host depends on several virulence factors encoded by many genes distributed on chromosomes and plasmids (Borges et al, 2019).
At the same time, antibiotic resistance in S. Enteritidisand S. Typhimurium has also become one of the most important public health problems worldwide. The emergence of resistance to broad-spectrum cephalosporins and fluoroquinolones is of great public health importance, considering that this class of antibiotics is critical for the management of human salmonellosis cases . This paper will review the role of poultry and their products that can act as a factor in the spread of multidrug resistant (MDR)Non-Typhoid Salmonella and aspects related to food safety with One Health approach to understand the impact on public health, animals, and the environment.

Salmonella
Bacteria from the genus Salmonella belong to the family Entrobacteriaceae, Gram negative, facultative anaerobic, non-producing spores, have petrichous flagella and motile (Cosby et all, 2015), except forS. Gallinarumand S. Pullorum (Jajere, 2019). Salmonella is able to reduce nitrate to nitrite, well grown at of 35-40 (Cosby et all, 2015), can metabolize nutrients chemoorganotrophically and unable to ferment lactose. Salmonella has the broadest predilection for the digestive tract of humans and animals. Salmonella is divided into 2 groups of species, Salmonella enterica and Salmonella bongori, based on the differences in their 16S rRNA. Based on biochemical properties and genomic linkages, Salmonella enterica was classified into six subspecies (S.

Salmonellaare
zoonotic and are generalist hosts that can infect various warm-blooded animals, including humans (Arya et all, 2017). Salmonella serotypes, such as Enteritidis, Typhimurium, Newport, Heidelberg and Montevideo are known to contribute in Salmonellosis through their contamination of various food products including chicken, pork, eggs, vegetables and milk (Andino and Hanning, 2015). The distribution of Salmonella serotypes in various food products shown in table 1.

Virulence Factors Type III Scretion System (T3SS)
The main characteristics of virulence and factors in S. enterica serovars such as invasion or intracellular replication in host cells. These factors include flagella, capsule, plasmid, adhesion system and Type III Secretion System (T3SS) (Hassena et al, 2021). One of the major genetic elements, namely Salmonella Pathogenicity Island-1 (SPI1), determines the virulence ability among Salmonella serotypes (Lostroh and Lee, 2001). Enteropathogenic bacteria, including S. enterica have a type III secretion system (T3SS) which plays an important role in their virulence ability. This system allows the translocation of bacterial virulence proteins into the host cell cytosol (Akopyan et al., 2011)(Park et al., 2018. These proteins are known as effectors, which can modulate or interfere with various host cellular processes (Sun et al., 2016), facilitating bacterial colonization and survival (Feria et al., 2015). The central element of T3SS is the injectisome, a multi-protein machinery (Park et al., 2018) consisting of a needle complex (de Souza Santos and Orth, 2019). T3SS consists of a cylindrical basal body ~26 nm in diameter and ~32 nm in height (Kato et al., 2018), with a two-ring structure encompassing the bacterial inner and outer membranes (de Souza Santos and Orth, 2019). As well as the cytoplasmic structure that is used to sort effector proteins (Kato et al., 2018) and provide energy for the secretory process (Hu et al., 2017). T3SS measures about 3.5 MDa spanning the double membrane and protruding into the extracellular space. About 25 structural proteins and additional proteins are required for their assembly (Puhar et al., 2014).

Salmonella Pathogenicity Island (SPI)
The virulence factor of S. entericais encoded by a conserved gene on Salmonella Pathogenicity Island (SPI) (Askoura and Hegazy, 2020). The existence of this SPI is obtained horizontally (Eade et al., 2019) which occurs through conjugation, transformation and transduction mechanisms (Pradhan and Negi, 2019) (Zishiri et all, 2016). There are five main SPIs (1-5) (Lamas et all, 2018), of which SPI-1 and SPI-2 contain a large number of virulence genes related to intracellular pathogenesis and coencode T3SS (Wang et all, 2020). SPI-1 is 40-kb in size, which includes 39 genes encoding T3SS-1, their chaperone and effector proteins. As well as several transcriptional regulators that control the expression of virulence genes inside and outside SPI-1 (Lou et all, 2019). The expression level of the SPI-1 gene is dependent on the HilA regulator encoded SPI-1, which directly activates the expression of the SPI-1 structural gene (Golubeva et al., 2016). SPI-1 T3SS is expressed by Salmonella in the early stages of infection, which can stimulate inflammation (Kim et al., 2018). In contrast, SPI-2 is required by Salmonella for growth in different host cells (Dhanani et all, 2015) (Jennings et all, 2017), including macrophages (Fardsanei et all, 2017). SPI-3 is used by Salmonella in the process of intracellular proliferation and Mg2+ uptake and systemic spread. And SPI-5 which plays an important role in the development of the infection process and intracellular survival (Bertelloni et al., 2017).

Virulence Plasmid
Non-Typhoidal Salmonella also carries a virulence plasmid (Dos Santos et all, 2019). Salmonella virulence plasmids are 50-90 kb in size with a low copy number (1-2 plasmids per chromosome) that can be transmitted (Lobato-Márquez, 2016). In S. Typhimurium, it has a size of ~90 kb (pSLT) (Passaris et all, 2018) with an 8 kb region and a highly converted gene sequence, termed the Salmonella plasmid virulence (spv) locus (Silva et al., 2017) and functions as serum resistance, adhesion, colonization and promote the growth and reproduction of bacteria in host cells and tissues (Wu et all, 2016). Virulence plasmids also encode genes required for systemic infection (Abraham et all, 2018), such as the pef gene (plasmid encoded fimbriae), which plays a role in adhesion to crypt epithelial cells and induction of proinflammatory responses (Silva et al., 2017); the spv gene which is used to suppress the host's innate immune response (Abraham et al., 2018)

Fimbriae
Through different virulence factors, Salmonella also develops an adhesin function on the fimbriae which are used to attach to host cells (Rehman et al, 2019). Salmonella uses its fimbriae through interaction with proteins on host cell receptors, to be able to carry out adhesion and colonization in the intestine (Hansmeier et al, 2017). Fimbriae are generally 0.5-10 nm long and 2-8 nm wide (Rehman et all, 2019). Fimbriae in Salmonella are generally grouped into classes according to their assembly mechanism, namely (1) curli fimbriae which are assembled through a nucleation-precipitation (N/P) process through deposition of the main subunit with the extracellular media nucleator (Dufresne et al., 2018); (2) chaperoneusher (CU) fimbriae are assembled using periplasmic chaperones and usher outer periplasmic membranes, to form the main subunit into the final external filament (Rehman et all, 2019) and (3) type IV fimbriae are assembled on the inner and outer membranes. extended through the periplasm and outer membrane to the extracellular environment. These fimbriae can be assembled or disassembled using ATP (Dufresne et al., 2018). However, fimbriae in S. Enteritidishave different structures, these fimbriae are assembled using the CU system and consist of several subunits (Quan et al., 2019). In addition, it is also classified based on different clades, γ, κ, π, β, α and σ (Rehman et all, 2019). Among these clades, the lpf and fim genes belong to subclade γ1, sef subclade γ3, pef subclade κ and sdc in subclade σ (Quan et al., 2019).

Flagella
Bacterial motility comes from organelles called flagella. More than 40 genes are responsible for flagella assembly and its motor function (Kubori et al., 1992). In each strain of Salmonella, each has flagella of different types of H-antigens, with different primary structures (Asakura et al., 1966). Flagella are morphologically divided into three parts: filaments, hooks and basal structures (Aizawa, 1996). The basal body is an important part of flagella motor function (Kubori et al., 1992) and is morphologically divided into an inner membrane ring (MS), a rod and an outer ring (LP) (Jones and Macnab, 1990) which are embedded in the outer membrane. then extends into the periplasmic space. The MS ring structure is considered as the rotor, the rod as the shaft and the LP ring as the bushings. (Kubori et al., 1992). Filaments and hooks are on the outside of the cell (Aizawa, 1996), while the basal structure is anchored on the outer and inner membranes (Kawamoto et al., 2013). In Salmonella, the genes responsible for flagella formation are about 50 genes grouped into 17 operons, where each operon is divided into three classes according to the order of expression (Alzawa, 1996). The gene is flg, flh, fli or flj. While the genes responsible for flagella function are encoded by flagellar rotation (mot), chemotaxis (che) genes, and transmembrane signal transduction of chemotactic stimuli (tar, trg, tsr, etc.) (Kutsukake et al., 1990). Distribution of Virulence Factors among Salmonella Species is presented in table 2.  S. Enteritidis is known to be very well adapted to the cage and egg environment. Salmonella infection in poultry is often caused by S. Enteritidis which transmits vertically and transovarianly. In addition, contamination caused by S. Typhimurium and other serovars occurs externally by penetrating the egg shell (Andino and Hanning, 2015). In addition, the surface of chicken meat can be contaminated with Salmonella from intestinal contents, faecal material or from crosscontamination during the slaughter process (da Cunha-Neto et al, 2018). (Banggera et all, 2019). In the few cases of salmonellosis outbreaks that occurred in Australia, the United States and the United Kingdom, a large number of outbreaks of gastrointestinal infections due to foodborne disease were associated with eggs. The pattern of consumption of raw or undercooked eggs is often associated with cases of salmonellosis. S.Enteritidis is a major concern for most of the poultry industry (Chousalkar and Gole, 2016).
Through a number of studies in various countries, the prevalence of Non-Typhoid Salmonella (NTS) contamination in chicken meat in the Hanoi area, Vietnam is 71.8% with the highest percentage of contamination occurring in traditional markets (90%) compared to supermarkets (52.6%). (Nhung et al, 2018). 14.89% of chicken meat in Northern India, much higher than the 7.01% poultry faeces sample (Sharma et all, 2019) and 63.6% in chicken meat in traditional markets in Guangdong region, China (Zhang et al., 2018) and 26.70% in the Malaysian region (Thung et all, 2016). Contamination among Salmonella species in poultry products shown in table 3.

Mobile Genetic Element -Transposons and Insertion Sequences
Transposons (TN) are transposable elements that include small cryptic elements or insertion sequences (IS), transposons and transposition bacteriophages that facilitate the movement of DNA fragments from one location to another on bacterial chromosomes and plasmids (Tripathi andTripathi, 2017) (Partridge et al., 2018). Insertion sequences (IS) are sandwiched between short, inverted and repeating sequences flanking the coding region of the gene (Brown-Jaque et al., 2015). From 10-40 base pairs at both ends (Sultan et al., 2018). The entire DNA fragment from one IS element to another is transposed as a complete unit (Brown-Jaque et al., 2015). Insertion sequences (IS) are classified according to different nuclease catalytic domains, namely DD (E/D), HUH, phosphoserine and phosphotyrosine site-specific recombinase, which can be found in transportase, invertase or resolvase (Razavi et al., 2020 (Tripathi and Tripathi, 2017).

Mobile Genetic Element -Integron
Integrons are mobile DNA elements consisting of site-specific recombination systems (Meng et al., 2017) that are capable of integrating, assembling and expressing resistance-related genes in the gene cassette structure (Tripathi and Tripathi, 2017). As well as transferring from one bacterium to another (Meng et al., 2017). In general, integrons have structures in the form of (1) intl genes resistance determinants (streptomycinspectomycin), trimethoprim (Sultan et al., 2018). Multidrug resistance mechanism mediated by horizontal gene transfer presented in table 5.

MULTIDRUG RESISTANT SALMONELLA IMPLICATTIONS ON HUMAN HEALTH
Antimicrobial resistance is considered as one of the main threats to human health, as well as a major concern for food safety, which in its transmission involves the food chain (Tollefson and Miller, 2000). Antibiotics are used in animal food production to promote growth, prevent (prophylaxis), treat (therapeutic), and control (metaphylaxis) infectious diseases (Bengtsson and Greko, 2014). The extensive use of antibiotics in animal production systems (Nair et al., 2018) has contributed to increased selection pressure on the emergence and spread of multidrug resistance Salmonella isolates (Parisi et al., 2018). Most human infections by MDR Non-typhoidal Salmonella (NTS) are generally of foodborne origin, with animals as reservoirs of resistance and retail meat acting as carriers of human disease (Glenn et al., 2013). The presence of antibiotics in food consumed by humans has its own implications for the development of antibiotic resistance by the human gut microbiome (Lekshmi et al, 2017). The complex route of transmission between farm animals, humans and transfer of AMR genes between bacteria makes the reservoir of AMR genes in livestock poses risks to animal and human health, considering that some of these resistant ones are zoonotic (Argudin et al, 2017). Increased antimicrobial resistance in Salmonella sp. as foodborne bacteria contribute to increasing human health consequences, such as increasing cases of foodborne disease and increasing number of treatment failures (Anderson et al., 2003).
Antibiotic resistance in Salmonella is strongly influenced by strains:S. Enteritidis, S. Typhimurium, S. Typhimurium monophasic, S. Infantis and S. Derby, where all five can be found in humans and food products such as poultry meat and eggs (Peruzyet al., 2020).

RISK FACTORS OF MULTIDRUG RESISTANNCE SALMONELLA
In recent years, the risk factors associated with multidrug resistance Salmonella isolates have received considerable attention (Hoelzeret al., 2010) (Jibril et al., 2020).
Meat consumption and contact in farm environment are also important risk factors for humans (Hoelzerel., 2010). Food contact with surfaces, chicken slaughtered process and hygiene practices in wet market (Moe et al., 2017). Low or higher temperature during broiler transportation to the slaughterhouse (Arsenault et al., 2007) have been associated with the risk factors in chicken carcasses.

CONTROL AND PREVENTION
The application of Good Farming Practices (GFPs), Good Agricultural Practices (GAPs) and Good Manufacturing Practices (GMPs) is very important as a preventive measure against contamination caused by Salmonella spp. from producers to consumers (Camino Feltes et al, 2017). To reduce the risk of AMR, surveillance of resistance in humans and foods of animal origin is important to measure the long-term effectiveness of any control measures. An integrated surveillance system helps measure and compare the prevalence rate of antibiotic resistance in the food chain (Thapa et all, 2019). For the poultry industry, it is very important to control Salmonella related to food safety, such as (i) this zoonotic agent can cause foodborne disease which has a negative impact on public health; (ii) Salmonella is important in terms of antimicrobial resistance; (iii), these bacteria can cause international restrictions on the import and export of chickens and eggs; and (iv) can reduce the health level of poultry (Pulido-Landínez, 2019). At the hatchery level, disinfection of eggs with chemicals, ozone, UV irradiation, electrostatic charging, pulsed light and plasma gas is known to prevent Salmonella contamination. Not only that, passive and active immune response-based strategies, feed modification and feed management can reduce the susceptibility of poultry to infections caused by Salmonella (Dar et all, 2017). To reduce the spread of antibiotic resistance through the food chain and the environment, the use of antibiotics must be carried out effectively, through: (i) limiting antibiotics to only therapeutic uses; (ii) ensure accurate disease diagnosis; (iii) using appropriate antibiotic agents; (iv) use of appropriate dosage and duration of treatment; (v) prohibit the use of antibiotics as growth promoters; and (vi) the use of antibiotics based on a veterinarian's prescription (Sarter et all, 2015).

Foodborne
disease caused by Salmonella contamination in poultry products (meat and eggs) has consequences for public health problems.
The pathogenicity of Salmonella is controlled by various virulence genes found on chromosomes and plasmids, which affect attachment to host cells, invasion and replication in the host body and toxin production. In addition, poultry products have been considered to be a major source of multidrug resistant (MDR) Salmonella contamination which is influenced by genes related to virulence and antimicrobial resistance (AMR) related to the potential virulence of bacteria. The increase in the number of antimicrobial-resistant Salmonella strains has become a significant public health problem. Increased risk factors and rates of multidrug resistance Salmonella contamination has an impact on increasing public health problems and the risk of death from bacteremia which requires the integration of housing biosecurity, hygienic slaughter practices and good food product processing, to ensure food safety from farm to  Alvarez-Ordóñez, A., Bolton, D., Bover-Cid, S., Chemaly, M., De Cesare, A., Herman, L., Hilbert, F., Lindqvist, R., Nauta, M., Peixe, L., Ru, G., Simmons, M., Skandamis, P., Suffredini, E., Dewulf, J., Hald, T., Michel, V., Niskanen, T., Ricci, A., Snary, E., Boelaert, F. and