**2. OS has dual role in diseases**

OS offers protection against invading microorganisms, and on the other hand can cause damage to cells/tissues.

Erythrocytes being heme rich, provides the invading bacteria a rich source of iron for its metabolism. Bacteria have evolved mechanisms to scavenge the iron through hemolytic toxins and heme scavenging systems [85–87]. Erythrocytes counteract the bacteria through the production of ROS. The α and β sub units of hemoglobin possess high affinity binding sites for lipopolysaccharides (LPS), and leads to macrophage cytokine production and enhances the macrophage binding to LPS. Hemoglobin in μM concentrations have shown to inhibit yeast and bacterial growth through the production of ROS [88–90].

The protection conferred by hemoglobin against invading organisms have a detrimental effect in case of pathological states. Elevations in free hemoglobin is associated with increased mortality. Globin is associated with the protective properties, whereas heme triggers the proinflammatory response. During endotoxemia, the protective effects of hemoglobin is attributed to globin scavenging free heme, which has the property of activating a host of proinflammatory proteins and ROS generation. It has also been shown to increase the transcription of proinflammatory genes by 100-fold [91–93].

## **3. Modulations in erythrocytes due to OS**

#### **3.1 ROS cascade**

The ROS cascade in erythrocytes begins with the autooxidation of hemoglobin (Hb) into methemoglobin (MetHb). Oxidation of MetHb results in the formation of sulfhemoglobin (SulfHb) along with superoxide anion (O2). Erythrocytes have an innate antioxidant system that detoxifies the cells. The superoxide generated is detoxified by superoxide dismutase into H2O and H2O2, which is further detoxified by catalase and glutathione peroxidase (with the help of glutathione) into H2O and O2. Erythrocytes also contain non-enzymatic antioxidants such as glutathione, ascorbic acid (Vit C), and α-tocopherol (Vit E). This antioxidant mechanism helps the erythrocyte's survival in an oxygen-rich environment. Glutathione redox system: reduced glutathione (GSH), glutathione disulfide (GSSG), glutathione reductase (GR), glutathione peroxidase plays an important role in inactivating the ROS [94, 95].

#### **3.2 Erythrocyte aging**

The lifespan of erythrocytes *in vivo* is around 120 days. About 1% of the erythrocytes are cleared or phagocytized from circulation every day in humans. The membrane of erythrocytes comprises of proteins (50%), lipids (40%), and carbohydrates (10%). Hb comprises about 95% of the total cytoplasmic proteins. The membrane-associated proteins include band 3 (anion exchanger), band 4.1, spectrin, ankyrin, and glycophorin C which are responsible for maintaining the structure of the cell [94].

As the reticulocyte ages and transforms into erythrocyte, various changes occur in its membrane, composition, appearance and catalytic functions [96]. Aging of erythrocytes is associated with the changes in physical, biochemical and physiological properties. Thus, aged cells are more prone to be trapped and ultimately

**39**

microorganisms [108].

**4.1 Bacterial infections**

against the invading microorganisms [109].

*Modulations in Oxidative Stress of Erythrocytes during Bacterial and Viral Infections*

tions [99–102]. There is also an increase in the amount of glycated Hb.

aging, resulting in decreased function and survival [97].

tion in infected mice may increase aging of erythrocytes [104].

destroyed during microcirculation [97]. During aging, a decrease in the cell volume and hemoglobin is observed. The old erythrocytes also increase in density as they bind to autologous IgG (immunoglobulin G), that serves as an initiator for the removal of senescent erythrocytes. The binding of antibodies is also associated and triggered by changes to the anion exchanger, Band 3. There is a decline in sulphate transport with age, thus hampering the binding of ankyrin to Glyceraldehyde 3-phosphate dehydrogenase (GAPDH), a key enzyme in glycolysis [98]. The N- and C- terminal regions of Band 3 are conformationally changed during aging that results in the formation of neoantigens, which serve as a senesce marker. It is also observed that damaged hemoglobin (Hb) bind to band 3 resulting in cluster forma-

Aging erythrocytes also lose water, 2,3-BPG, ATP, proteins, Hb and vesicles that cause the cell volume and surface charge to decrease. There is also loss of some of the surface materials such as sialic acids that alter the structure and function of the membrane. These sialic acids are 90% *N*-acetylneuraminic acid (NANA) which accords the electrical charge to the cells [103]. These senescent RBCs also expose membrane phosphatidylserine. An increase in erythrocyte OS causes accelerated

The study of Igbokwe *et al*., 1994 reported the effects of *Trypanosoma brucei* infection in mice. They concluded that a lowered ability to prevent lipid peroxida-

**4. Bacterial and viral infections causing variations in erythrocytes**

Erythrocytes were assumed to only function as innate oxygen carriers. However, recent studies have shown them to be important in modulating the innate immune response [105–107]. Mammalian erythrocytes, unlike the erythrocytes of birds, amphibians and fishes, are enucleate and lack major cell organelles. The organelles of the latter modulate the immune response through production of cytokine like factors, upregulating viral response genes and pathogen sequestering through phagocytosis. Mammalian erythrocytes on the other hand modulate the innate immune response through generation of reactive oxygen species (ROS) to promote inflammatory and autoimmune response against invading

Minasyan, 2014 highlighted the role of erythrocytes in conferring bacterial immunity, which is comparable to phagocytic leukocytes as: (i) they are more numerous in number; (ii) fend off microorganisms repeatedly without injury; and (iii) resistant to infection. Erythrocytes have a longer lifespan when compared with leukocytes as well as being produced at a faster rate. The cytosol of erythrocytes is unfavorable to parasitic organisms such as chlamidiae, mycoplasmas, rickettsiae, viruses, etc. Erythrocytes elevate to the primary line of defense against bacterial infections when: (i) there is a presence of massive microbial load; (ii) ineffective recruitment of phagocytes; (iii) faster proliferation and spread of the microorganisms than the phagocytes' capacity; and (iv) ineffectiveness of the phagocytes

Sepsis is one of the most recognized life-threatening dysfunctions that is caused due to infections and is the leading cause for mortality in non-cardiac ICUs (intensive care units) around the world. Sepsis may be caused by gram-positive,

*DOI: http://dx.doi.org/10.5772/intechopen.98236*

#### *Modulations in Oxidative Stress of Erythrocytes during Bacterial and Viral Infections DOI: http://dx.doi.org/10.5772/intechopen.98236*

destroyed during microcirculation [97]. During aging, a decrease in the cell volume and hemoglobin is observed. The old erythrocytes also increase in density as they bind to autologous IgG (immunoglobulin G), that serves as an initiator for the removal of senescent erythrocytes. The binding of antibodies is also associated and triggered by changes to the anion exchanger, Band 3. There is a decline in sulphate transport with age, thus hampering the binding of ankyrin to Glyceraldehyde 3-phosphate dehydrogenase (GAPDH), a key enzyme in glycolysis [98]. The N- and C- terminal regions of Band 3 are conformationally changed during aging that results in the formation of neoantigens, which serve as a senesce marker. It is also observed that damaged hemoglobin (Hb) bind to band 3 resulting in cluster formations [99–102]. There is also an increase in the amount of glycated Hb.

Aging erythrocytes also lose water, 2,3-BPG, ATP, proteins, Hb and vesicles that cause the cell volume and surface charge to decrease. There is also loss of some of the surface materials such as sialic acids that alter the structure and function of the membrane. These sialic acids are 90% *N*-acetylneuraminic acid (NANA) which accords the electrical charge to the cells [103]. These senescent RBCs also expose membrane phosphatidylserine. An increase in erythrocyte OS causes accelerated aging, resulting in decreased function and survival [97].

The study of Igbokwe *et al*., 1994 reported the effects of *Trypanosoma brucei* infection in mice. They concluded that a lowered ability to prevent lipid peroxidation in infected mice may increase aging of erythrocytes [104].
