scholarly journals Lethal avian influenza A (H5N1) virus replicates in pontomedullary chemosensitive neurons and depresses hypercapnic ventilatory response in mice

2019 ◽  
Vol 316 (3) ◽  
pp. L525-L536 ◽  
Author(s):  
Jianguo Zhuang ◽  
Na Zang ◽  
Chunyan Ye ◽  
Fadi Xu
Keyword(s):  
Viral Infection ◽  
Carotid Body ◽  
Influenza A ◽  
Tryptophan Hydroxylase ◽  
Ventilatory Response ◽  
Severe Depression ◽  
Infection Period ◽  
Hypercapnic Ventilatory Response ◽  
H5n1 Influenza ◽  
Neurokinin 1

The highly pathogenic H5N1 (HK483) viral infection causes a depressed hypercapnic ventilatory response (dHCVR, 20%↓) at 2 days postinfection (dpi) and death at 7 dpi in mice, but the relevant mechanisms are not fully understood. Glomus cells in the carotid body and catecholaminergic neurons in locus coeruleus (LC), neurokinin 1 receptor (NK1R)-expressing neurons in the retrotrapezoid nucleus (RTN), and serotonergic neurons in the raphe are chemosensitive and responsible for HCVR. We asked whether the dHCVR became worse over the infection period with viral replication in these cells/neurons. Mice intranasally inoculated with saline or the HK483 virus were exposed to hypercapnia for 5 min at 0, 2, 4, or 6 dpi, followed by immunohistochemistry to determine the expression of nucleoprotein of H5N1 influenza A (NP) alone and coupled with 1) tyrosine hydroxylase (TH) in the carotid body and LC, 2) NK1R in the RTN, and 3) tryptophan hydroxylase (TPH) in the raphe. HK483 viral infection blunted HCVR by ∼20, 50, and 65% at 2, 4, and 6 dpi. The NP was observed in the pontomedullary respiratory-related nuclei (but not in the carotid body) at 4 and 6 dpi, especially in 20% of RTN NK1R, 35% of LC TH, and ∼10% raphe TPH neurons. The infection significantly reduced the local NK1R or TPH immunoreactivity and population of neurons expressing NK1R or TPH. We conclude that the HK483 virus infects the pontomedullary respiratory nuclei, particularly chemosensitive neurons in the RTN, LC, and raphe, contributing to the severe depression of HCVR and respiratory failure at 6 dpi.

scholarly journals Neurokinin-1 receptor activation is sufficient to restore the hypercapnic ventilatory response in the Substance P-deficient naked mole-rat

2020 ◽  
Vol 318 (4) ◽  
pp. R712-R721 ◽  
Author(s):  
Maxwell S. Clayson ◽  
Maiah E. M. Devereaux ◽  
Matthew E. Pamenter
Keyword(s):  
Substance P ◽  
Network Architecture ◽  
Ventilatory Response ◽  
Receptor Activation ◽  
Whole Body ◽  
Hypercapnic Ventilatory Response ◽  
Exogenous Substance ◽  
Mole Rat ◽  
Freely Behaving ◽  
Neurokinin 1

Naked mole-rats (NMRs) live in large colonies within densely populated underground burrows. Their collective respiration generates significant metabolic carbon dioxide (CO2) that diffuses slowly out of the burrow network, creating a hypercapnic environment. Currently, the physiological mechanisms that underlie the ability of NMRs to tolerate environmental hypercapnia are largely unknown. To address this, we used whole-body plethysmography and respirometry to elucidate the hypercapnic ventilatory and metabolic responses of awake, freely behaving NMRs to 0%–10% CO2. We found that NMRs have a blunted hypercapnic ventilatory response (HCVR): ventilation increased only in 10% CO2. Conversely, metabolism was unaffected by hypercapnia. NMRs are insensitive to cutaneous acid-based pain caused by modified substance P (SP)-mediated peripheral neurotransmission, and SP is also an important neuromodulator of ventilation. Therefore, we re-evaluated physiological responses to hypercapnia in NMRs after an intraperitoneal injection of exogenous substance P (2 mg/kg) or a long-lived isoform of substance P {[pGlu5-MePhe8-MeGly9]SP(5-11), DiMe-C7; 40–400 μg/kg}. We found that both drugs restored hypercapnia sensitivity and unmasked an HCVR in animals breathing 2%–10% CO2. Taken together, our findings indicate that NMRs are remarkably tolerant of hypercapnic environments and have a blunted HCVR; however, the signaling network architecture required for a “normal” HCVR is retained but endogenously inactive. This muting of chemosensitivity likely suits the ecophysiology of this species, which presumably experiences hypercapnia regularly in their underground niche.

scholarly journals Activation of Opioid μ-Receptors in the Commissural Subdivision of the Nucleus Tractus Solitarius Abolishes the Ventilatory Response to Hypoxia in Anesthetized Rats

2011 ◽  
Vol 115 (2) ◽  
pp. 353-363 ◽  
Author(s):  
Zhenxiong Zhang ◽  
Jianguo Zhuang ◽  
Cancan Zhang ◽  
Fadi Xu
Keyword(s):  
Carotid Body ◽  
Nucleus Tractus Solitarius ◽  
Ventilatory Response ◽  
Hypercapnic Ventilatory Response ◽  
Study Results ◽  
Spontaneously Breathing ◽  
Similar Decrease ◽  
Ventilatory Response To Hypoxia ◽  
Μ Receptor ◽  
Carotid Body Denervation

Background : The commissural subnucleus of the nucleus tractus solitarius (comNTS) is a key region in the brainstem responsible for the hypoxic ventilatory response (HVR) because it contains the input terminals of the carotid chemoreceptor. Because opioids inhibit the HVR via activating central μ-receptors that are expressed abundantly in the comNTS, the authors of the current study asked whether activating local μ-receptors attenuated the carotid body-mediated HVR. Methods : To primarily stimulate the carotid body, brief hypoxia (100% N2) and hypercapnia (15% CO2) for 10 s and/or intracarotid injection of NaCN (10 μg/100 μl) were performed in anesthetized and spontaneously breathing rats. These stimulations were repeated after: (1) microinjecting three doses of μ-receptor agonist [d-Ala2, N-Me-Phe4, Gly-ol]-Enkephalin (DAMGO) (approximately 3.5 nl) into the comNTS; (2) carotid body denervation; and (3) systemic administration of DAMGO (300 μg/kg) without and with previous intracomNTS injection of d-Phe-Cys-Tyr-d-Trp-Arg-Thr-Pen-Thr-NH2, a μ-receptor antagonist. Results : Study results showed that DAMGO at 0.25 and 2.5, but not 0.025 mM, caused a similar decrease in baseline ventilation (approximately 12%). DAMGO at 0.25 mM largely reduced (64%) the HVR, whereas DAMGO at 2.5 mM abolished the HVR (and the VE response to NaCN) and moderately attenuated (31%) the hypercapnic ventilatory response. Interestingly, similar HVR abolition and depression of the hypercapnic ventilatory response were observed after carotid body denervation. Blocking comNTS μ-receptors by d-Phe-Cys-Tyr-d-Trp-Arg-Thr-Pen-Thr-NH2 significantly attenuated the HVR depression by systemic DAMGO with little change in the DAMGO modulatory effects on baseline ventilation and the hypercapnic ventilatory response. Conclusion : The data suggest that opioids within the comNTS, via acting on μ-receptors, are able to abolish the HVR by affecting the afferent pathway of the carotid chemoreceptor.

Carotid body chemosensitivity is not attenuated during cold water diving

2021 ◽  
Author(s):  
Hayden W. Hess ◽  
David Hostler ◽  
Brian M. Clemency ◽  
Erika St. James ◽  
Blair D. Johnson
Keyword(s):  
Cold Stress ◽  
Carotid Body ◽  
Cold Water ◽  
Ventilatory Response ◽  
Water Immersion ◽  
Hypoxic Ventilatory Response ◽  
Hyperbaric Chamber ◽  
Time Points ◽  
Hypercapnic Ventilatory Response ◽  
End Tidal

Introduction: Tonic carotid body (CB) activity is reduced during exposure to cold and hyperoxia. We tested the hypotheses that cold water diving lowers CB chemosensitivity and augments CO2 retention more than thermoneutral diving. Methods: Thirteen subjects (age: 26±4 y; BMI: 26±2 kg/m2) completed two, four-hour head out water immersion protocols in a hyperbaric chamber (1.6 ATA) in cold (15°C) and thermoneutral (25°C) water. CB chemosensitivity was assessed using brief hypercapnic ventilatory response (CBCO2) and hypoxic ventilatory response (CBO2) tests pre-dive, 80 and 160 min into the dives (D80 and D160, respectively), immediately following and 60 min post-dive. Data are reported as an absolute mean (SD) change from pre-dive. Results: End-tidal CO2 pressure increased during both the thermoneutral water dive (D160: +2(3) mmHg; p=0.02) and cold water dive (D160: +1(2) mmHg; p=0.03). Ventilationincreased during the cold water dive (D80: 4.13(4.38) and D160: 7.75(5.23) L·min-1; both p<0.01) and was greater than the thermoneutral water dive at both time points (both p<0.01). CBCO2 was unchanged during the dive (p=0.24) and was not different between conditions (p=0.23). CBO2 decreased during the thermonutral water dive (D80: -3.45(3.61) and D160: -2.76(4.04) L·min·mmHg-1; p<0.01 and p=0.03, respectively), but not the cold water dive. However, CBO2 was not different between conditions (p=0.17). Conclusion: CB chemosensitivity was not attenuated during the cold stress diving condition and does not appear to contribute to changes in ventilation or CO2 retention.

scholarly journals A Conserved Residue, Tyrosine (Y) 84, in H5N1 Influenza A Virus NS1 Regulates IFN Signaling Responses to Enhance Viral Infection

Viruses ◽  
2017 ◽  
Vol 9 (5) ◽  
pp. 107 ◽  
Author(s):  
Ben Wang ◽  
Lianhu Wei ◽  
Lakshmi Kotra ◽  
Earl Brown ◽  
Eleanor Fish
Keyword(s):  
Viral Infection ◽  
Influenza A Virus ◽  
Influenza A ◽  
H5n1 Influenza ◽  
Conserved Residue

scholarly journals Epidemiological characteristics of four common respiratory viral infections in children

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Guohong Zhu ◽  
Dan Xu ◽  
Yuanyuan Zhang ◽  
Tianlin Wang ◽  
Lingyan Zhang ◽  
...  
Keyword(s):  
Respiratory Tract ◽  
Viral Infection ◽  
Influenza A ◽  
Multiple Infection ◽  
Influenza B ◽  
Preschool Period ◽  
Significant Difference ◽  
Different Seasons ◽  
Tract Infections ◽  
Epidemiological Characteristics

Abstract Background Viruses are the main infectious agents of acute respiratory infections in children. We aim to describe the epidemiological characteristics of viral pathogens of acute respiratory tract infections in outpatient children. Methods From April 2018 to March 2019, the results of viral detection using oral pharyngeal swabs from 103,210 children with acute respiratory tract infection in the outpatient department of the Children’s Hospital, Zhejiang University School of Medicine, were retrospectively analyzed. Viral antigens, including adenovirus (ADV), influenza A (FLUA), influenza B (FLUB) and respiratory syncytial virus (RSV), were detected by the colloidal gold method. Results At least one virus was detected in 38,355 cases; the positivity rate was 37.2%. A total of 1910 cases of mixed infection with two or more viruses were detected, and the positivity rate of multiple infection was 1.9%. The ADV positivity rate was highest in the 3–6-year-old group (18.7%), the FLUA positivity rate was highest in the > 6-year-old group (21.6%), the FLUB positivity rate was highest in the > 6-year-old group (6.6%), and the RSV positivity rate was highest in the < 1-year-old group (10.6%). There was a significant difference in the positivity rate of viral infection among different age groups (χ2 = 1280.7, P < 0.001). The rate of positive viral infection was highest in winter (47.1%). The ADV infection rate was highest in spring (18.2%). The rates of FLUA and FLUB positivity were highest in winter (28.8% and 3.6%, respectively). The rate of RSV positivity was highest in autumn (17.4%). The rate of positive viral infection in different seasons was significantly different (χ2 = 6459.1, P < 0.001). Conclusions Viral infection rates in children differ for different ages and seasons. The positivity rate of ADV is highest in the preschool period and that of RSV is highest in infants; that of FLU increases with age. The total positive rate of viral infection in different seasons is highest in winter, as is the rate of FLU positivity.

scholarly journals Effect on Virulence and Pathogenicity of H5N1 Influenza A Virus through Truncations of NS1 eIF4GI Binding Domain

2010 ◽  
Vol 202 (9) ◽  
pp. 1338-1346 ◽  
Author(s):  
Hongbo Zhou ◽  
Jiping Zhu ◽  
Jiagang Tu ◽  
Wei Zou ◽  
Yong Hu ◽  
...  
Keyword(s):  
Influenza A Virus ◽  
Influenza A ◽  
Binding Domain ◽  
H5n1 Influenza

scholarly journals Characterization of a Human H5N1 Influenza A Virus Isolated in 2003

2005 ◽  
Vol 79 (15) ◽  
pp. 9926-9932 ◽  
Author(s):  
Kyoko Shinya ◽  
Masato Hatta ◽  
Shinya Yamada ◽  
Ayato Takada ◽  
Shinji Watanabe ◽  
...  
Keyword(s):  
Hong Kong ◽  
Avian Influenza ◽  
Influenza A Virus ◽  
Influenza A ◽  
Mainland China ◽  
Virus Infections ◽  
Influenza A Viruses ◽  
H5n1 Avian Influenza Virus ◽  
H5n1 Influenza ◽  
Avian Influenza A Virus

ABSTRACT In 2003, H5N1 avian influenza virus infections were diagnosed in two Hong Kong residents who had visited the Fujian province in mainland China, affording us the opportunity to characterize one of the viral isolates, A/Hong Kong/213/03 (HK213; H5N1). In contrast to H5N1 viruses isolated from humans during the 1997 outbreak in Hong Kong, HK213 retained several features of aquatic bird viruses, including the lack of a deletion in the neuraminidase stalk and the absence of additional oligosaccharide chains at the globular head of the hemagglutinin molecule. It demonstrated weak pathogenicity in mice and ferrets but caused lethal infection in chickens. The original isolate failed to produce disease in ducks but became more pathogenic after five passages. Taken together, these findings portray the HK213 isolate as an aquatic avian influenza A virus without the molecular changes associated with the replication of H5N1 avian viruses in land-based poultry such as chickens. This case challenges the view that adaptation to land-based poultry is a prerequisite for the replication of aquatic avian influenza A viruses in humans.

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