**3. Chronic infection of** *P. aeruginosa*

Upon infection, the host decreases iron levels in the blood [99]; this iron deficiency regulates a great number of bacterial virulent genes like alginate, the most relevant virulence factor, for *P. aeruginosa* survival [100]. In the lung, iron deficiency turns on AlgQ, the bacterial biofilm production gene, also known as AlgR2 [101, 102], under the Pfr A regulation that assists to the formation of two kinds of cytoplasmic aggregates: large vacuole-like bodies and smaller granules containing iron in association with oxygen or phosphate, very likely polyPi [103]. This leads to the RSCV type of *P. aeruginosa.* Under these conditions, the bacteria secrete alginate, a linear polysaccharide of d-mannuronic acid linked to l-guluronic acid [104].

The first gene described for the biosynthesis of alginate was the phosphomannose isomerase and GDP-mannose dehydrogenase (AlgD) that catalyze the conversion of GDP-mannose to GDP-mannuronic acid [105]. Upon oxygen limitation, *P. aeruginosa* utilizes nitrate or arginine as electron acceptors, via the succinylarginine pathway [106, 107]. The AlgD expression is tightly regulated by several environmental sources including nitrogen, O2, Pi, NaCl, etc. Although the regulation of AlgD has been extensively studied, it is not completely understood, and eradication of chronic infection greatly depends on control of alginate production.

Several authors have studied the AlgD regulation, **Figure 6** shows a 20-years breach in the finding of AlgD regulators. More positive regulators have been identified, such as AlgR that is upregulated by NaCl and also by the nitrogen source [108]. AlgD is also under the same promoter than PLC, which is sensitive to the nitrogen source [109] that regulates the anaerobiosis genes. These genes detect the ratio

**Figure 6.** *Regulators of AlgD in alginate production. Negative and positive regulators found up-today.*

of glutamine to 2-ketoglutarate, which is dependent on O2 availability [108, 110]. Another positive regulator of AlgD is AlgU [111], but the only negative regulator known is the RpoN, a sigma factor, that regulates nitrogen metabolism. RpoN is increased by disruption of pyrimidine synthesis and decreased by the supplementation with uracil, showing that a high level of RpoN, in the RSCV form, may block the alginate biosynthesis [110, 112].

Studies on the biosynthetic pathway of biofilms show that chelation of iron by lactoferrin destabilizes the bacterial membrane [113], which combined with xylitol hinders the ability of the bacteria to respond to iron deficiency [101], showing some promise for CF treatment.

### **4. Conclusions**

*P. aeruginosa* is a relevant pathogen given its widespread prevalence across different organs. The latent menace it poses for inpatients is a liability for institutions. For this, and the negative prognosis that *P. aeruginosa* infections in CF patients has, it is one of the subjects more researched for the last 40 years. The efforts have resulted in understanding the process of invasion, immune response, and bacterial tactics to achieve chronic infection. The complexity of the metabolic changes caused by the contact between the host and the bacteria is so extensive that the selection of variables for in vitro studies is difficult since the production of biofilm by *P. aeruginosa* seems to be regulated by everything, O2, N2, Fe2+, Pi, and NaCl. This multiregulatory network is still a puzzle to be resolved.

Scientists agree that suppression of alginate production is vital to treat CF patients, but in 40 years of research, little has been achieved in suppressing its production *in vivo.*

## **5. Perspectives**

The advancement of techniques with high output data like microarrays, proteomes, and mass spectrometry are closing the breach among the different approaches that have been used to tackle *P. aeruginosa* infections. For example, mass-spectrometry has verified through metabolite detection the metabolic pathways studied by molecular biologists and enzymologists. The integration of these studies with the physicians is needed to assess the areas that show more promises to control alginate production and *P. aeruginosa* eradication after it became a chronic infection.

**41**

**Author details**

Sandra Grumelli

Córdoba, Argentina

provided the original work is properly cited.

\*Address all correspondence to: sgrumelli@yahoo.com

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

Independent Researcher, Centro de Investigaciones en Medicina Respiratoria,

*Host-Pathogen Interaction in the Lung of Patients Infected with Pseudomonas aeruginosa*

*DOI: http://dx.doi.org/10.5772/intechopen.84657*

*Host-Pathogen Interaction in the Lung of Patients Infected with Pseudomonas aeruginosa DOI: http://dx.doi.org/10.5772/intechopen.84657*
