**7. How helminths defend themselves against pathogens**

Although the mechanisms by which different bacteria affect the resistance of worm to pathogens are poorly understood, helminths have developed a number of different procedures to survive: (1) Behavioral defense: In this case, the worm detects olfactory stimuli, recognizes odors, and modifies its behavior by olfactory learning and imprinting [20]. (2) Barrier mechanism: The muscular pharynx grinder provides a physical barrier against pathogens, which protects them by disrupting the engulfed microbes [21]. (3) Production of soluble molecules: Examples of antimicrobial proteins and peptides in response to microbial infection [22]. (4) Direct inhibition of pathogens: Exerts a commensal-mediated protective effect on *C. elegans* [23]. (5) RNA interference: *Orsay* virus (OV) is a natural pathogen of *C. elegans*. The worm develops specific protection against this virus via the antiviral RNAi response. This mechanism not only inhibits vertical OV transmission, but also promotes transgenerational inheritance of antiviral immunity [24]. (6) Innate immunity involving signaling pathways: Specific responses that protect and repair against the collateral damage caused by ROS are critical for a successful attack against pathogens. Thus, there is a connection between the generation of ROS by Ce-Duox1/BLI-3 and the upregulation of a protective transcriptional response by SKN-1 [25]. (7) Oxidative damage: The secretion of ROS by gut epithelia [25]. ROS are known to be involved in tissue damage. This is because of the imbalance between the antioxidizing defenses of the organisms and the oxygen intermediaries produced in cells during aerobic metabolism and/or host inflammatory defenses against some pathogens.

NADPH oxidases, whose biological function lies in electron transport, are also a major source of ROS. These enzymes are multi-pass transmembrane proteins that *Oxygen and Redox Reactions Contribute to the Protection of Free-Living and Parasite Helminths… DOI: http://dx.doi.org/10.5772/intechopen.102542*

catalyze the reduction of extracellular or luminal oxygen by intracellular NADPH to generate superoxide anions (O2•) [26]. NADPH oxidases have been discovered in macrophages as a defense mechanism against pathogens, but today it is known that they are widely distributed in different kingdoms with multiple biological functions. The importance of these enzymes in aerobic organisms has led to the discovery of the NOX/DUOX family of NADPH oxidases, which includes three NOX subfamilies: ancestral type, NOX5-like, and DUOX [27]. DUOX isoforms that presumably developed from the NOX5-like subfamily are known as dual oxidases because they have both a peroxidase homology domain and a gp91phox domain. This last domain is the heme-binding subunit of the superoxide-generating NADPH oxidase, the catalytic moiety; thus, DUOXs produce anion superoxide (O2•) and hydrogen peroxide (H2O2) by transferring one and two electrons, respectively, from intracellular NADPH to extracellular oxygen. DUOX is the only type of NOX present in *C. elegans*. The worm encodes two Duox genes (bli-3 and duox-2) that share an amino acid sequence with 94% identity to each other and approximately 30% to human Duox 1 and 2. It is known that *C. elegans* intestinal cells, like mammalian phagocytes, produce ROS, such as O2• and H2O2, via DUOXs as an antimicrobial response [3].

Therefore, *C. elegans* may be able to exert lipid peroxidation in the lipid membrane of micro pathogens in an effort to kill them, as has been described in prokaryotes and other eukaryote parasite-host relationships in the past.

### **8. The importance of lipid peroxidation**

Lipid peroxidation comprises a chain of reactions involving the oxidative degradation of lipids. It is the process in which free radicals, such as O2•, "steal" electrons from the lipids in cell membranes, resulting in cell damage. This process evolved from a free radical chain reaction mechanism, which comprised three steps: initiation, propagation, and termination. In the first step, O2• interacts with polysaturated fatty acids. This O2• is dismuted by superoxide dismutase, and in addition to hydrogen atoms, it breaks down into ordinary molecular oxygen and H2O2. Then, H2O2 in the presence of Fe2+ produces hydroxyl anions (OH•) via the Fenton reaction. The OH• takes away allylic hydrogens from the polyunsaturated fatty acid chains to obtain a radical carbon (L•). Then, the easy reaction with oxygen molecules by L• gives rise to the peroxyl radical (LOO•). When hydrogens are removed from polyunsaturated fatty acid neighbors, this LOO• results in the formation of lipid hydroperoxide (LOOH). The propagation step occurs when LOO• interacts with other polyunsaturated fatty acids, resulting in the formation of further lipid radicals and H2O2. Additionally, the catalysis of H2O2 by Fe2+ makes results in the formation of alkoxy and peroxy radicals during propagation step, with this secondary free radical production beginning another lipid hydrogen peroxide chain. Termination occurs when two radicals are conjugated, the result of which is a non-radical product.

The *C. elegans* model provides an opportunity to gain insights into how free-living helminths and parasite helminths exert this strategy to protect themselves against oxidative stress, even if the ROS are self-produced, as in *C. elegans*, or by the host response, as in human parasite helminths. In addition, the concept of lipid peroxidation can be explained practically since lipid peroxidation starts with the same oxidative molecules in any organism.

Due the short life of *C. elegans* compared with humans, the exertion of lipid peroxidation against micro pathogens could be considered an acute response, if a short one, as it is sufficient to damage the worm's own tissues. In other words, collateral damage can result from the processes by which worms are trying to kill micro pathogens. In human helminthiasis is a rule to see the development of chronic infections besides lipid peroxidation.

### **9. DUOX/NADPH oxidases in toxicity and signal transduction**

*C. elegans* is known to express antioxidant genes for protection against its autooxidative response, as described previously [28]. Human helminth parasites may also exert similar procedures for protection against oxidative stress. Therefore, understanding how *C. elegans* resist their own protective oxidative response could provide insights into how helminthiasis chronicity evolved in humans.

In this sense, Hoeven et al. [25] found that aerobic organism evolution works in a balanced dualism. For example, when the Earth's atmosphere became oxidant, living forms, including older forms of free-living helminths, developed an extremely complex cellular signal mechanism to manage oxygen toxicity. This permitted them to kill their adversary while surviving the collateral damage at the same time; this strategy is very clever and clearly observed in *C. elegans*. Upon exposure to *P. aeruginosa* and *E. faecalis*, *C. elegans* uses DUOX/1BLI-3 to kill pathogens by producing ROS. In addition, as DUOX/1BLI-3 is activated to kill pathogens found in the intestine of helminths, SKN-1 (Skinhead family member 1) transcription factor, a member of the Cap'n'collar (CNC) protein family, is simultaneously activated to avoid tissue damage [29].

Transcription factors belonging to this group of proteins play a crucial role in protecting cells against oxidative stress. Under physiological conditions, they remain in the cytoplasm in the inactive form or are degraded. However, under oxidative stress conditions, they are translocated to the nucleus and bind to DNA in the antioxidant response element (ARE) motif. Consequently, genes encoding cytoprotective proteins, such as low-molecular-weight antioxidant proteins (i.e., thioredoxin, ferritin, and metallothionein), responsible for protecting cells against the action of ROS, are transcribed. *C. elegans* SKN-1 has been extensively studied, with studies finding that this transcription factor is orthologous with the nuclear factor erythroid 2 (NFE2) related factor 2 (Nrf2). They are both members of the CNC subfamily of the basic leucine zipper (bZip) transcription factors [30].

Both transcription factors are highly conserved proteins with functions similar to those of the promoters of oxidative-stress-related genes. In fact, Nrf2 and SKN-1 regulate phase II detoxification genes needed to defend against oxidative stress and electrophilic xenobiotics. With this detoxification system, worms can solubilize lipophilic xenobiotics or endobiotics via cytochrome P450s (CYPs) and short-chain dehydrogenases (SDHs), two classic enzymes of the phase I detoxification step. Reactive products, including ROS originating from the original toxic molecules, are detoxified, either via metabolization or conjugation, by the phase II system using UDP-glucuronosyl/glucosyl transferases (UDP) or glutathione transferases (GSTs), among others. Afterward, conjugated toxins are eliminated from cells by phase III proteins, including ATP-binding cassette (ABC) and other transporters.

Thus, similar to Nrf2, SKN-1 controls many critical detoxification processes directly as glutathione transferase enzymes (GSTs).

*Oxygen and Redox Reactions Contribute to the Protection of Free-Living and Parasite Helminths… DOI: http://dx.doi.org/10.5772/intechopen.102542*
