**9. Antiviral activity of β-defensin-2 in respiratory infections**

The HBD2 was initially studied as an antibacterial peptide, and its antiviral activity has been recently demonstrated. The notion was that it only acted in enveloped viruses, but other studies have proven that they also act against naked viruses and any type of genome DNA, RNA and retroviruses. The mechanisms of antiviral inactivation have been classified as direct and indirect. The direct ones occur when HBD2 binds to the viral membrane by electrostatic attraction, causing pore formation and lysis of microorganism. The indirect mechanism occurs when it inactivates an intracellular pathway of the virus replication cycle or when there is recruitment of immune cells that contribute to their antiviral activity [2].

Acute respiratory infections caused by viruses are very common, causing high rates of mobility and mortality. There are few studies that relate to HBD2 and viral infection, and some of them are presented in the following paragraphs.

**67**

*Multifunctional Activity of the β-Defensin-2 during Respiratory Infections*

The influenza virus belongs to the Orthomyxoviridae family and renders acute respiratory infection affecting mainly children and adults. It is an RNA virus, enveloped and has the ability to mutate rapidly, causing epidemics and pandemics [136]. Influenza virus induces the production of HBD2 in the epithelial cells of the respiratory tract *in vivo* and *in vitro* [137]. In the *in vitro* study with infected MDCK cells with influenza virus, recombinant murine β-defensin-2 prevents infection by blocking the entry of the virus. The lungs of murine model infected with influenza virus showed an increased expression of β-defensin and therefore confer protection

This virus belongs to the family Paramyxoviridae and affects principally infants, young children and older adults causing bronchiolitis and pneumonia. VSR has a high rate of morbidity and mortality having RNA enveloped virus of negative sense. There are no vaccines available and only fewer antivirals available which have been

The human lung cells (A549) infected with RSV expressed HBD2 [140]. The expression of the peptide depends on the activation of NF-kB and the action of TNF produced by the virus. The elimination of the virus is due to damage to the

The adenoviruses belong to the Adenoviridae family; 51 serotypes divided into six species have been recognized (HAd A-F). Species B, C and E produce respiratory infections. Adenoviruses are double-stranded linear DNA viruses, lack envelope and replicate in the nucleus, and their genome has a size of 36 kb. These viruses spread rapidly in closed environments such as military camps, orphanages, boarding schools and prisons. The acute respiratory infections are transmitted mainly by aerosols and by direct inoculation through fingers. Although this disease is benign and with little severity, the infection might be severe in immunosuppressed patients afflicted with HIV and with kidney transplants. The HBD2 inactivates the infection for adenovirus *in vitro*; the mechanisms of action are not yet known due to lack of *in* 

The rhinovirus is the main cause of the common cold belonging to Picornaviridae family. They are small, single-chained, naked RNA viruses.

replication appears essential for the expression of peptide [141].

Respiratory infections caused by rhinoviruses are associated with asthma exacerbations in children and adults. Rhinovirus infection in the A549 cells (human lung cells) and bronchial epithelial cells induces the expression of HBD2. The virus

Initially, β-defensin-2 was considered an antimicrobial peptide. The advance in the study of these molecules has made it possible to know that β-defensin-2 is a peptide with multiple functions. However, its role in the pathology of respiratory

*DOI: http://dx.doi.org/10.5772/intechopen.80611*

**9.1 Influenza virus**

against infection [21, 138].

seen ineffective [22, 139].

membrane.

**9.3 Adenovirus**

*vivo* studies [140].

**10. Conclusions**

**9.4 Rhinovirus**

**9.2 Respiratory syncytial virus (VSR)**

*Multifunctional Activity of the β-Defensin-2 during Respiratory Infections DOI: http://dx.doi.org/10.5772/intechopen.80611*

### **9.1 Influenza virus**

*Immune Response Activation and Immunomodulation*

strains and fewer therapeutic agents [128].

pathogenesis of disease.

**8.12 Sepsis**

and 10% have active disease. There are many difficulties due to highly resistant

However, HBD2 is suggested to play an important role in the control of the disease by direct inactivation of the bacteria or as an immunostimulant in vaccines. This bacterium mainly infects macrophages and lung epithelial cells. The *in vitro* studies have shown that *M. tuberculosis* induces the expression of HBD2 in human lung epithelial cells (A549) and is associated with the destruction of bacteria [129, 130]. The transfection of monocytes derived from macrophages with the HBD2 gene increases the ability to control the growth of *M tuberculosis* when compared with non-transfected cells [131]. Children infected with *M. tuberculosis* present high concentrations of HBD2 in bronchoalveolar lavage suggesting its involvement in the

Results are favorable in animal model studies in mice, mice were vaccinated with DNA vaccines (gene encoding β-defensin-2 and antigens of *M tuberculoisis*) and months later were challenged with *M tuberculoisis* strains. The level of protection was evaluated by survival, and tissue damage. DNA vaccines showed protection with significant higher survival and less tissue damage in the mice [132]. When a person is infected with *M. tuberculosis*, the microenvironment is reduced in oxygen; this triggers the expression of the vitamin D receptor and HBD2 inhibits the growth bacteria.

Other signaling pathways that have been discovered are in monocytes through the CD40L and IFN receptors that converge in the activation of vitamin D. HBD2 is

The infectious diseases can cause severe sepsis and the patient's immune system to suffer drastic changes. This study investigated the concentration and the expression of HBD2 in peripheral whole blood cells from patients with severe sepsis. They detected that the peripheral blood cells expressed a decrease in the expression of HBD2. The patient serum showed higher concentrations of HBD2. The patients with severe sepsis have severe inflammatory processes and the proinflammatory cytokines are at high concentrations (IL-1 and TNF); these cytokines also induce the expression of HBD2. It is suggested that these cytokines may be involved in the overproduction of HBD2 in the blood of patients with sepsis. The decreased HBD2 induced in peripheral blood cells was not associated with decreased plasma levels, suggesting that peripheral blood cells do not represent the exclusive source of released protein [135].

The lack of local oxygen benefits the macrophage for its elimination.

**9. Antiviral activity of β-defensin-2 in respiratory infections**

of immune cells that contribute to their antiviral activity [2].

infection, and some of them are presented in the following paragraphs.

The HBD2 was initially studied as an antibacterial peptide, and its antiviral activity has been recently demonstrated. The notion was that it only acted in enveloped viruses, but other studies have proven that they also act against naked viruses and any type of genome DNA, RNA and retroviruses. The mechanisms of antiviral inactivation have been classified as direct and indirect. The direct ones occur when HBD2 binds to the viral membrane by electrostatic attraction, causing pore formation and lysis of microorganism. The indirect mechanism occurs when it inactivates an intracellular pathway of the virus replication cycle or when there is recruitment

Acute respiratory infections caused by viruses are very common, causing high rates of mobility and mortality. There are few studies that relate to HBD2 and viral

expressed and acts against the bacterium *M. tuberculosis* [134].

**66**

The influenza virus belongs to the Orthomyxoviridae family and renders acute respiratory infection affecting mainly children and adults. It is an RNA virus, enveloped and has the ability to mutate rapidly, causing epidemics and pandemics [136].

Influenza virus induces the production of HBD2 in the epithelial cells of the respiratory tract *in vivo* and *in vitro* [137]. In the *in vitro* study with infected MDCK cells with influenza virus, recombinant murine β-defensin-2 prevents infection by blocking the entry of the virus. The lungs of murine model infected with influenza virus showed an increased expression of β-defensin and therefore confer protection against infection [21, 138].

#### **9.2 Respiratory syncytial virus (VSR)**

This virus belongs to the family Paramyxoviridae and affects principally infants, young children and older adults causing bronchiolitis and pneumonia. VSR has a high rate of morbidity and mortality having RNA enveloped virus of negative sense. There are no vaccines available and only fewer antivirals available which have been seen ineffective [22, 139].

The human lung cells (A549) infected with RSV expressed HBD2 [140]. The expression of the peptide depends on the activation of NF-kB and the action of TNF produced by the virus. The elimination of the virus is due to damage to the membrane.

#### **9.3 Adenovirus**

The adenoviruses belong to the Adenoviridae family; 51 serotypes divided into six species have been recognized (HAd A-F). Species B, C and E produce respiratory infections. Adenoviruses are double-stranded linear DNA viruses, lack envelope and replicate in the nucleus, and their genome has a size of 36 kb. These viruses spread rapidly in closed environments such as military camps, orphanages, boarding schools and prisons. The acute respiratory infections are transmitted mainly by aerosols and by direct inoculation through fingers. Although this disease is benign and with little severity, the infection might be severe in immunosuppressed patients afflicted with HIV and with kidney transplants. The HBD2 inactivates the infection for adenovirus *in vitro*; the mechanisms of action are not yet known due to lack of *in vivo* studies [140].

#### **9.4 Rhinovirus**

The rhinovirus is the main cause of the common cold belonging to Picornaviridae family. They are small, single-chained, naked RNA viruses. Respiratory infections caused by rhinoviruses are associated with asthma exacerbations in children and adults. Rhinovirus infection in the A549 cells (human lung cells) and bronchial epithelial cells induces the expression of HBD2. The virus replication appears essential for the expression of peptide [141].

## **10. Conclusions**

Initially, β-defensin-2 was considered an antimicrobial peptide. The advance in the study of these molecules has made it possible to know that β-defensin-2 is a peptide with multiple functions. However, its role in the pathology of respiratory

diseases is unclear. During the infectious processes of the respiratory epithelium, HBD2 is expressed by the effect of the infection, and it has been described that it may be closely associated with the severity of the disease. The study of HBD2 during viral respiratory infections is unclear, so it is necessary to continue investigating the role of this molecule in the immune response activated by viral infections.
