**7. Conclusion**

found that hyphae induce higher amounts of NETs than the yeast form, after 4 hours of incubation. *Candida albicans* hyphae stimulate cells through autophagy but not ROS, whereas the yeast form induces NETs through autophagy and ROS. *C. albicans β-glycans* induce NETosis

In 2015, Rocha et al. described that the opportunistic fungus *Cryptococcus neoformans*, which possesses a glucuronoxylomannan (GMX)-containing capside, precludes this fungus to be phagocytosed by neutrophils. These authors also demonstrated that the acapsular strain of *Cryptococcus neoformans*, which harbor glucuronoxylomannogalactan (GMXgal), is capable of inducing NETs. In contrast, the capsular strain does not induce

The release of NETs by the acapsular strain of *Cryptococcus neoformans* is dependent on ROS generation and the PAD4 enzyme. The capsular strain also inhibits PMA-induced NETs formation [51]. NETs release has also been observed in response to *Cryptococcus gattii* stimulation. Analysis of *Cryptococcus neoformans* susceptibility to acapsular strain-induced NETs showed that NETs diminished colony-forming units (CFUs) by 80% in the capsular strain and by 54%

*Paracoccidioides brasiliensis* and *Paracoccidioides lutzii* are fungi of the *Paracoccidioides* genus that cause high mortality and morbidity by the systemic mycosis Paracoccidioidomycosis (PCM), mostly in Latin American countries. Della Coletta et al. [52] have investigated the role of neutrophil extracellular traps on these fungi, reporting the formation of NETs by the yeasts

Viruses have an extraordinary ability to evade the immune system, and the innate immune system is regarded as the first line of defense. Innate immune cells recognize a wide variety of pathogens through their pattern-recognition receptors (PRRs) that include Toll-like receptors (TLRs), NOD-like receptors (NLRs), and RIG-like receptors (RLRs) that recognize pathogenassociated molecular patterns (PAMPs). Several PRRs recognize viral ligands such as TLR-3, TLR-7, TLR-8, RIG-1, and MDA5, and the activation of these PRRs induces the synthesis of antiviral interferons (types I and II), tumor necrosis factor α, interleukin-15, and interleu-

The role of NETs in the control of several bacterial infections has been broadly analyzed. However, research on their role in viral infections remains scarce. It has recently been shown that viral infections or virus-derived molecules may act as strong inducers of NETs. Several viruses that induce the formation of NETs have been identified. In some cases, NETs neutralize the viral particles by the MPO or the granule-derived defensins, associated to NETs. The α-defensin protein directly inhibits the influenza virus replication and protein synthesis [56].

in the case of the acapsular strain. For this, it is necessary that NETs contain MPO.

**6. Neutrophil extracellular traps in viral infections**

by an ROS-independent mechanism [49, 50].

**5.3. Cryptococcus neoformans**

36 Role of Neutrophils in Disease Pathogenesis

the release of NETs [51].

*P. brasiliensis* and *P. luttzii*.

kin-18 [53–55].

Anti-microbial properties of NETs have been shown for bacteria, protozoa, fungus, and virus. Understanding how neutrophil extracellular traps (NETs) limit the growth of some infectious agents, whereas, apparently, they have no effect on others, and how NETs may cause tissue damage and contribute to the development of pathologies, such as autoimmune diseases, will help to exploit their anti-pathogen properties at full, and to limit their pathogenic effects, in clinical settings. It is quite likely that this research field will continue providing exciting findings.

## **Author details**

Maximina B. Moreno-Altamirano\*, Christian E. Cruz-Gómez and Lluvia E. López-Luis

\*Address all correspondence to: bertha.moreno.altamirano@gmail.com

Department of Immunology, National School of Biological Sciences (ENCB), National Politechnic Institute (IPN), Mexico City, Mexico

## **References**


[12] Yousefi S, Gold JA, Andina N, Lee JJ, Kelly AM, Kozlowski E, Schmid I, Straumann A, Reichenbach J, Gleich GJ, Simon HU. Catapult-like release of mitochondrial DNA by eosinophils contributes to antibacterial defense. Nature Medicine. 2008;**14**(9):949-953

**Author details**

38 Role of Neutrophils in Disease Pathogenesis

**References**

Maximina B. Moreno-Altamirano\*, Christian E. Cruz-Gómez and Lluvia E. López-Luis

Department of Immunology, National School of Biological Sciences (ENCB), National Po-

[1] Kaufmann SH. Immunology's foundation: The 100-year anniversary of the Nobel Prize

[2] Nathan C. Neutrophils and immunity: Challenges and opportunities. Nature Reviews

[3] Fuchs TA, Abed U, Goosmann C, et al. Novel cell death program leads to neutrophil

[4] Gupta AK, Joshi MB, Philippova M, et al. Activated endothelial cells induce neutrophil extracellular traps and are susceptible to NETosis-mediated cell death. FEBS Letters.

[5] Neeli I, Khan SN, Radic M. Histone deimination as a response to inflammatory stimuli

[6] Rodríguez-Espinosa O, Rojas-Espinosa O, Moreno-Altamirano MM, López-Villegas EO, Sánchez-García FJ. Metabolic requirements for neutrophil extracellular traps formation.

[7] Brinkmann V, Reichard U, Goosmann G, Fauler B, Uhlemann Y, Weiss DS, Weinrauch Y, Zychlinsky A. Neutrophil extracellular traps kill bacteria. Science. 2004;**30**:1532-1535

[9] Yang H, Biermann MH, Brauner JM, Liu Y, Zhao Y, Hermann M. New insights into neutrophil extracellular traps: Mechanisms of formation and role in inflammation. Frontiers

[10] Remijsen Q, Berghe TW, Wirawan E, Asselbergh B, et al. Neutrophil extracellular traps cell death requires both autophagy and superoxide generation. Cell Research.

[11] von Köckritz-Blickwede, Goldmann O, Thulin P, Heinemann K, Norrby-Teglund A, Rohde M, Medina E. Phagocytosis-independent antimicrobial activity of mast cells by

in neutrophils. Journal of Immunopharmacology. 2008;**180**:1895-1902

[8] Yipp BG, Kubes P. NETosis: How vital is it? Blood. 2013;**122**(16):2784-2794

means of extracellular trap formation. Blood. 2008;**111**(6):3070-3080

to Paul Ehrlich and Elie Metchnikoff. Nature Immunology. 2008;**9**:705-712

\*Address all correspondence to: bertha.moreno.altamirano@gmail.com

extracellular traps. Journal of Cell Biology. 2007;**176**:231-241

Immunology. 2015;**145**(2):213-224. DOI: 10.1111/imm.12437

litechnic Institute (IPN), Mexico City, Mexico

Immunology. 2006;**6**:173-182

2010;**584**:3193-3197

in Immunology. 2016;**7**:302

2011;**21**:290-304


[36] Camicia G. Neutrophil extracellular traps: A 2-faced host defense mechanism. Medicina Clinica. 2012;**140**:2

[24] Aulik NA, Hellenbrand KM, Czuprynski CJ. Mannheimia haemolytica and its leukotoxin cause macrophage extracellular trap formation by bovine macrophages. Infection

[25] Branzk N, Lubojemska A, Hardison SE, Wang Q, Gutierrez MG, Brow GD, Papayannopoulos V. Neutrophils sense microbe size and selectively release neutrophil extracellular traps in

[26] Ramos-Kichik V, Mondragón-Flores R, Mondragón-Castelán M, Gonzalez-Pozos S, Muñiz-Hernandez S, Rojas-Espinosa O, Chacón-Salinas R. Estrada-Parra S, Estrada-García I. Neutrophil extracellular traps are induced by Mycobacterium tuberculosis.

[27] Francis RJ, Butler RE, Stewart GR. Mycobacterium tuberculosis ESAT-6 is a leukocidin causing Ca2+ influx, necrosis and neutrophil extracellular trap formation. Cell Death and

[28] Yuen J, Pluthero FG, Douda DN, Riedl M, Cherry A, Ulanova M, Kahr WH, Palaniyar N, Licht C. NETosing neutrophils activate complement both on their own NETs and bacteria via alternative and Non-alternative pathways. Frontiers in Immunology.

[29] Manda A, Pruchniak MP, Araźna M, Demkow UA. Neutrophil extracellular traps in physiology and pathology. Central European Journal of Immunology. 2014;**39**(1):116-121

[30] Malachowa N, Kobayashi SD, Freedman B, Dorward DW, DeLeo FR. Staphylococcus aureus leukotoxin GH promotes formation of neutrophil extracellular traps. The Journal

[31] Cogen AL, Yamasaki K, Muto J, Sánchez KM, Crotty Alexander I, Tanios J, et al. Staphylococcus epidermidis antimicrobial delta-toxin (phenol-soluble modulin-gamma) cooperates with host antimicrobial peptides to kill group a streptococcus. PLoS One.

[32] Köckritz-Blickwede Maren von, Blodkamp S, Nizet V. Interaction of bacterial exotoxins with neutrophil extracellular traps: Impact for the infected host. Frontiers in

[33] Abi Abdallah D, Denkers E. Neutrophils cast extracellular traps in response to proto-

[34] Abi Abdallah D, Lin C, Ball C, King M, Duhamel G, Denkers E. *Toxoplasma gondii* triggers release of human and mouse neutrophil extracellular traps. Infection and Immunity.

[35] Baker VS, Imade GE, Molta NB, Tawde P, Pam SD, Obadofin MO, Sagay SA, Egah DZ, Iya D, Afolabi BB, Baker M, Ford K, Ford R, Roux KH, Keller 3rd TC. Cytokineassociated neutrophil extracellular traps and antinuclear antibodies in *Plasmodium falciparum* infected children under six years of age. Malaria Journal. 2008;**7**:41. DOI:

response to large pathogens. Nature Immunology. 2014;**15**(11):1017-1025

and Immunity. 2012;**80**(5):1923-1933

Tuberculosis. 2009;**89**:29-37

of Immunology. 2013;**191**:6022-6029

Microbiology. 2016;**7**:402

2011;**80**(2):768-777

10.1186/1475-2875-7-41

2010;**5**:e8557. DOI: 10.1371/journal.pone.0008557

zoan parasites. Frontiers in Immunology. 2012;**3**:382

Disease. 2014;**5**:1474

40 Role of Neutrophils in Disease Pathogenesis

2016;**7**:137

