Host defense against infection

Cellular and humoral components are specific barriers of the immune (innate and acquired) system as protective mechanisms against infection. But additionally, the innate immune system also relies on anatomical features. Although these two immune responses cover distinct functions, there is interplay of components and they complement each other (Mayer, 2006).

 Anatomical barriers

The anatomical barriers are the immediate physical obstacles of the pathogenic invaders and they are very effective in preventing colonization of tissues by pathogens. These barriers consist of mechanical, chemical and biological factors.

Mechanical Factors: Mechanical anatomical barriers include epithelial barriers such as the skin as the first impermeable barrier to infection, followed by mucous membranes which line the body’s cavities including the nose, mouth and the gastrointestinal tract. The scull and thoracic cage also provide protection to the internal organs from exposure to pathogens. Ciliary movements help to keep the gastrointestinal tract free of microorganisms as well as the flushing action of tears and saliva protects eyes and mouth from infection (Boyton and Openshaw, 2002; Coussens and Werb, 2001; Mayer, 2006).

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Chemical Factors: Fatty acids, low molecular weight anti-microbial peptides and the low pH in sweat as well as gastric secretions prevent growth of bacteria. Lysozyme and phospholipase found in tears, saliva and nasal secretions can breakdown bacterial membranes. Antimicrobial activity is possessed by defensins (host defense peptides) present in the lung and gastrointestinal tract. In addition, surfactants in the lung can act as opsonins (substances promoting uptake of particles by phagocytic cells) (Hankiewicz and Swierczek, 1974; Mayer, 2006; Moreau et al., 2001).

Biological factors: The microbiota of the skin or in the gastrointestinal tract play an important role to prevent colonization of pathogenic microorganisms by releasing toxic secretions or by competing with pathogens for nutrients or attachment to cell surfaces (Cho and Blaser, 2012; Gerritsen et al., 2011; Gorbach, 1990; Mayer, 2006; Salminen et al., 2005).

 Humoral barriers

Infection may occur once pathogens have penetrated tissues and the anatomical barriers are breached. In this moment, another innate defense mechanism comes into play namely acute inflammation (fast protective innate immune response that involves, blood vessels, molecular mediators and leukocyte recruitment to the infected tissue), which help to eliminate the initial cause of cell injury (microbial clearance), clear out necrotic cells and damaged tissues. In addition, a longer process of tissue repair (chronic inflammation) is also initiated (Ferencik and Stvrtinova, 1996; Mayer, 2006; Miyake and Kaisho, 2014).

Humoral factors play a key role in inflammation. These humoral factors are found in serum or they are formed at the site of infection. This innate immune response is characterized by an abnormal accumulation of fluid beneath the skin or in the cavities of the body (edema) and the recruitment of phagocytic cells at sites of infection (Ferencik et al., 2007; Mayer, 2006).

Complement system: It is the major humoral innate defense mechanism and, as it is named, helps or complements the ability of antibodies and phagocytic cells to clear pathogens from an organism. The complement system consists of a number of small proteins found in the blood, generally synthesized by the liver, and normally circulating as inactive precursors (pro-proteins). Plasma and membrane bound proteins of the complemented system include serum proteins, serosal proteins, and cell membrane receptors (Muller-Eberhard, 1988). The complement system can be activated by three pathways: The

19 classical (antigen-antibody reaction –adaptive response), the alternative (triggered by the fragment C3b) and the lectin pathway (triggered by Mannose Binding Lectin microorganism -MBL). The alternative and lectin pathways are part of the first line of defense in the innate immune response. The main functions of complement system are opsonization (enhancing phagocytosis of antigens), chemotaxis (attracting macrophages and neutrophils), cell lysis (rupturing membranes of foreign cells) and agglutination (clustering and binding of pathogens) (Dzik, 2010; Janeway et al., 2001; Rutkowski et al., 2010).

Coagulation system: The coagulation system is activated or not depending on tissue injury severity. Products of the coagulation system can contribute to the innate immune defense by increasing vascular permeability (acting as chemotactic agents for phagocytic cells) or because of their antimicrobial effect (Furie and Furie, 2007; Mayer, 2006).

Other humoral factors like lactoferrin, transferrin, interferons, lysozyme and Interleukin-1, either limit the replication or help in the clearance of microbial cells (Dussurget et al., 2014; Ganz et al., 2003; Schultz et al., 2002; Skaar, 2010; Vareille et al., 2011).

 Cellular barriers

The innate immune system as the first line of defense against invading pathogens comprises a particular set of cells prompt to be mobilized and battle microbes at the site of infection. The main line of defense in the innate immune system is the white blood cells (leukocytes) consisting of granulocytes (neutrophils, eosinophils, and basophils) and monocytes (which develop into macrophages). These leukocytes play a critical role in host defense and their recruitment to the site of infection is part of the inflammatory response.

Inflammatory mediators also include mast cells. These cells together regulate the inflammatory responses and signal the body to mount an inflammatory response for invading microorganisms. Thus, the inflammatory response is important in the regulation of phagocytic cells activation (Alberts et al., 2002).

Granulocytes: These cells are characterized by the presence of granules in their cytoplasm.

They are also called polymorphonuclear leukocytes (PMN) because of the varying shapes of the nucleus but often PMNs refer specifically to neutrophil granulocytes. Neutrophils are the most abundant granulocytes, followed by eosinophils, basophils, and mast cells.

Granulocytes have a common myeloid progenitor (granulocyte precursor) in the bone

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barrow during differentiation of blood cells (haematopoiesis). PMNs circulate in the bloodstream and must be signaled to leave the bloodstream and enter tissues, playing an important role during acute inflammation (Ley et al., 2007; Petri et al., 2008).

Granulocytes are recruited to the site of infection. Activation of these phagocytic cells results from microbes per se, from complement proteins, or from damaged tissue (chemotaxis). Invading organism are recognized and phagocytosed by neutrophils and eosinophils (specifically parasites), whereas basophils and mast cells contain abundant histamine, and other substances which contribute to the inflammatory response that helps fight invading organisms (Akuthota et al., 2008; Borregaard and Cowland, 1997; Hickey and Kubes, 2009; Stvrtinova et al., 2001).

Macrophages: In the myeloid lineage, monocytes (which differentiate into macrophages) together with lymphocytes constitute the mononuclear agranulocytes of the white blood cells. Macrophages represent a multi-functional cell type in innate immunity. Tissue macrophages and newly recruited monocytes contribute to bacterial clearance by recognition, phagocytosis and killing. Beyond their crucial role in the innate defense, they also are important to initiate specific (acquired or adaptive) defense mechanisms by acting as antigen-presenting cells, which are required for the induction of specific immune responses (Moldovan and Moldovan, 2005; North, 1970; Pinet et al., 2003). Furthermore, as scavengers, they play an important role in acute and chronic inflammation by removing dying or dead cells and cellular debris of the body as well as in wound healing (they replace PMNs as the predominant cells in the wound and phagocytose damage tissue) (Gurtner et al., 2008; Rodero and Khosrotehrani, 2010).

Natural killer cells: They are effector lymphocytes of the immune system with biological functions attributed to both innate and adaptive immunity. These cells as type of cytotoxic lymphocytes are critical to the innate immune system in viral infection and tumor development. NK cells are not part of the inflammatory response but important for cytolytic granule mediated cell apoptosis, antibody-dependent cell-mediated cytotoxicity, cytokine activation, tumor cell surveillance among other functions (Arina et al., 2007;

Iannello et al., 2008; Lodoen and Lanier, 2005; Terunuma et al., 2008; Vivier et al., 2011).

Denditric cells: The name of these cells refers to the branched projection ‘dendrites’ of their cell body. Their main function is to induce either immune tolerance or lymphocyte activation minimizing as well autoimmune reactions. They capture and process antigens,

21 migrate to lymphoid organs and secrete cytokines to initiate immune responses. These cells act as messengers between the innate and the adaptive immune systems (Banchereau and Steinman, 1998; McKenna et al., 2005).