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{{Hantavirus pulmonary syndrome}}
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{{Hantavirus infection}}
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==Overview==
==Overview==
Hantaviruses belong to the bunyavirus family of viruses. There are 5 genera within the family: bunyavirus, phlebovirus, nairovirus, tospovirus, and hantavirus. Each is made up of negative-sensed, single-stranded RNA viruses. All these genera include arthropod-borne viruses, with the exception of hantavirus, which is rodent-borne.
Hantavirus is usually transmitted via the inhalation of aerosolized [[viral]] antigens or [[rodent]] bites. The [[incubation period]] of hantavirus infection is of 9 to 33 days. Following inhalation, the virus replicates in pulmonary [[macrophages]] and [[Dendritic cell|dendritic cells]]. The primary target cells of hantavirus infection are [[endothelial cells]] of [[capillaries]]. Infection is followed by impairment of the barrier function of [[endothelial cells]], fluid extravasation, and subsequent [[organ failure]].


==Pathophysiology==
==Pathophysiology==
Like other members of the bunyavirus family, hantaviruses are enveloped viruses with a genome that consists of three single-stranded RNA segments designated S (small), M (medium), and L (large). All hantaviral genes are encoded in the negative (genome complementary) sense. The S RNA encodes the nucleocapsid (N) protein. The M RNA encodes a polyprotein that is cotranslationally cleaved to yield the envelope glycoproteins G1 and G2. The L RNA encodes the L protein, which functions as the viral transcriptase/replicase. Within virions, the genomic RNAs of hantaviruses are thought to complex with the N protein to form helical nucleocapsids, which circularize due to sequence complementarity between the 5' and 3' terminal sequences of each genomic segment.  
===Reservoir===
Each Hantavirus species is associated with a specific rodent in a given geographic region. Rodent subfamilies associated with hantaviruses include
*Arvicolinae (Europe)
*Murinae (Europe and Asia)
*Sigmodontinae (Americas)
===Transmission===
Hantavirus is usually transmitted via the inhalation of aerosolized viral antigens or rodent bites. Human to human transmission is seen in American Hantaviruses species (Andes virus).


Hantaviruses replicate exclusively in the host cell cytoplasm. Entry into host cells is thought to occur by attachment of virions to cellular receptors and subsequent endocytosis. Nucleocapsids are introduced into the cytoplasm by pH-dependent fusion of the virion with the endosomal membrane. Transcription of viral genes is initiated by association of the L protein with the three nucleocapsid species. In addition to transcriptase and replicase functions, the viral L protein is also thought to have an endonuclease activity that cleaves cellular messenger RNAs (mRNAs) for the production of capped primers used to initiate transcription of viral mRNAs. As a result of this "cap snatching," the mRNAs of hantaviruses are believed to be capped and contain nontemplated 5' terminal extensions. The viral N and L mRNAs are thought to undergo translation at free ribosomes, whereas the M mRNA is translated in the endoplasmic reticulum. G1 and G2 glycoproteins form heterodimers and are then transported from the endoplasmic reticulum to the Golgi complex, where glycosylation is completed. The L protein produces nascent genomes by replication via a positive-sense RNA intermediate. Hantavirions are believed to form by association of nucleocapsids with glycoproteins embedded in the membranes of the Golgi, followed by budding into the Golgi cisternae. Nascent virions are then transported in secretory vesicles to the plasma membrane and released by exocytosis.
===Incubation period===
The [[incubation period]] of hantavirus infection is of 9 to 33 days.<ref name="urlIncubation Period of Hantavirus Cardiopulmonary Syndrome - Volume 12, Number 8—August 2006 - Emerging Infectious Disease journal - CDC">{{cite web |url=https://wwwnc.cdc.gov/eid/article/12/8/05-1127_article |title=Incubation Period of Hantavirus Cardiopulmonary Syndrome - Volume 12, Number 8—August 2006 - Emerging Infectious Disease journal - CDC |format= |work= |accessdate=}}</ref>


'''Disease development'''
===Seeding===
Following inhalation, the virus replicates in pulmonary [[Macrophage|macrophages]] and [[Dendritic cells|dendritic cells.]]


Within 24 hours of initial evaluation, most patients develop some degree of hypotension and progressive evidence of pulmonary edema and hypoxia, usually requiring mechanical ventilation. The patients with fatal infections appear to have severe myocardial depression which can progress to sinus bradycardia with subsequent electromechanical dissociation, ventricular tachycardia or fibrillation.  
===Pathogenesis===
The pathogenesis of hantavirus infection can be described by impairment of the barrier function of [[endothelial cells]], fluid extravasation and subsequent organ
failure.<ref name="pmid23841977">{{cite journal |vauthors=Spiropoulou CF, Srikiatkhachorn A |title=The role of endothelial activation in dengue hemorrhagic fever and hantavirus pulmonary syndrome |journal=Virulence |volume=4 |issue=6 |pages=525–36 |year=2013 |pmid=23841977 |pmc=5359750 |doi=10.4161/viru.25569 |url=}}</ref>
====Impairment of the barrier function of endothelial cells====
* The primary target cells of hantavirus infection are [[endothelial cells]] of capillaries. Most commonly endothelial cells of [[lungs]] and [[heart]] are involved.
* Hantaviruses attach to beta-3 [[integrin]] receptors of endothelial cells and stimulate [[T cells]].<ref name="pmid9618541">{{cite journal |vauthors=Gavrilovskaya IN, Shepley M, Shaw R, Ginsberg MH, Mackow ER |title=beta3 Integrins mediate the cellular entry of hantaviruses that cause respiratory failure |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=95 |issue=12 |pages=7074–9 |year=1998 |pmid=9618541 |pmc=22743 |doi= |url=}}</ref><ref name="pmid12376753">{{cite journal |vauthors=Gavrilovskaya IN, Peresleni T, Geimonen E, Mackow ER |title=Pathogenic hantaviruses selectively inhibit beta3 integrin directed endothelial cell migration |journal=Arch. Virol. |volume=147 |issue=10 |pages=1913–31 |year=2002 |pmid=12376753 |doi=10.1007/s00705-002-0852-0 |url=}}</ref>
* Neutralizing antibody (NAbs) are produced as a result of stimulation and beta-3 [[integrins]] are inactivated.
* Inactivation of virus-bound beta-3-integrins contributes to deregulation of [[Vascular endothelial growth factor receptors|vascular endothelial growth facto]]<nowiki/>r receptor-2 (VEGFR2) and diminished antagonism of [[vascular endothelial growth factor]] (VEGFA).<ref name="pmid12368479">{{cite journal |vauthors=Geimonen E, Neff S, Raymond T, Kocer SS, Gavrilovskaya IN, Mackow ER |title=Pathogenic and nonpathogenic hantaviruses differentially regulate endothelial cell responses |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue=21 |pages=13837–42 |year=2002 |pmid=12368479 |pmc=129784 |doi=10.1073/pnas.192298899 |url=}}</ref>
* This leads to impairment of vascular endothelial (VE) cadherin expression and subsequent loss of endothelial barrier function.
* [[Platelet]]<nowiki/>s are consumed in high number in response to the damage to the endothelial layer resulting in [[thrombocytopenia]].


Hemodynamic compromise occurs a median of 5 days after symptom onset--usually dramatically within the first day of hospitalization. In contrast to HFRS, overt hemorrhage occurs rarely in HPS, although hemorrhage is occasionally seen in association with disseminated intravascular coagulation. In contrast to septic shock, HPS patients have a low cardiac output with a raised systemic vascular resistance. Poor prognostic indicators include a plasma lactate of greater than 4.0 mmol/L or a cardiac index of less than 2.2 L/min/m2 Whilst pulmonary edema and pleural effusions are common, multiorgan dysfunction syndrome is rarely seen. However, HPS patients sometimes have mildly impaired renal function. Survivors frequently become polyuric during convalescence and improve almost as rapidly as they decompensated.
====Fluid extravasation====
* Neutralizing antibody (NAbs) also inhibit innate type I [[interferon]] (IFN) responses of endothelial cells.
* This results in inhibition of upregulation of CD73 by [[Interferon|IFN-beta]] on endothelial cells and promotes vascular leakage.
====Multiorgan failure====
* Hantaviruses demonstrated to have an immunoreceptor tyrosine-based activation motif (ITAM) on their G1 envelope glycoproteins.
* Immunoreceptor tyrosine-based activation motif along with local T-cell [[cytokine]] production results in cellular downstream and immune cell dysfunction.<ref name="pmid9878011">{{cite journal |vauthors=Mori M, Rothman AL, Kurane I, Montoya JM, Nolte KB, Norman JE, Waite DC, Koster FT, Ennis FA |title=High levels of cytokine-producing cells in the lung tissues of patients with fatal hantavirus pulmonary syndrome |journal=J. Infect. Dis. |volume=179 |issue=2 |pages=295–302 |year=1999 |pmid=9878011 |doi=10.1086/314597 |url=}}</ref>
* Attachment of hantavirus to beta-2 integrin receptors on [[neutrophils]] also induces the release of neutrophil extracellular traps.
* Sensitized mononuclear cells infiltrate the [[lung]], myocardial interstitium, and [[spleen]] to produce [[cytokines]], particularly [[TNF-alpha]] and [[interferon-gamma]], resulting in [[pulmonary edema]] and [[myocarditis]]


'''Other Hantaviruses'''
== References ==
{{reflist|2}}


Several members of the hantavirus genus cause different forms of hemorrhagic fever with renal syndrome (HFRS), an ancient disease first described in Russia in 1913. The four viruses that are associated with HFRS, each named for the region from where they were first isolated, have different primary rodent hosts: Apodemus agrarius (the striped field mouse) for Hantaan virus, Rattus norvegicus (the Norway rat) and Rattus rattus (the black rat) for Seoul virus, Clethrionomys glareolus (the bank vole) for Puumala virus, and Apodemus flavicollis (the yellow-necked field mouse) for Dobrava virus. Hantaan virus from Korea and Dobrava virus from Slovenia are associated with a severe form of HFRS characterized by renal failure that can precede pulmonary edema and disseminated intravascular coagulation (DIC), with estimated mortality rates of 5% to 15%. A moderate form of HFRS caused by Seoul virus (which, along with its host, is distributed worldwide) is responsible for thousands of Eurasian cases annually. Serologic evidence for infection with Seoul-like hantaviruses has been found in rodents in major cities of the United States, and this virus was recently implicated in human cases of HFRS in Baltimore. One report has also associated Seoul virus with chronic renal disease. A mild form of HFRS, caused by Puumala virus, is responsible for nephropathia epidemica in Scandinavia, with an estimated mortality rate of 1% to 3%.
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{{reflist|2}}
http://www.cdc.gov/ncidod/diseases/hanta/hps/noframes/phys/virology.htm


http://www.cdc.gov/ncidod/diseases/hanta/hps/noframes/phys/clinical.htm
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==References==
{{Reflist|2}}
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Latest revision as of 21:57, 29 July 2020

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aditya Ganti M.B.B.S. [2]

Overview

Hantavirus is usually transmitted via the inhalation of aerosolized viral antigens or rodent bites. The incubation period of hantavirus infection is of 9 to 33 days. Following inhalation, the virus replicates in pulmonary macrophages and dendritic cells. The primary target cells of hantavirus infection are endothelial cells of capillaries. Infection is followed by impairment of the barrier function of endothelial cells, fluid extravasation, and subsequent organ failure.

Pathophysiology

Reservoir

Each Hantavirus species is associated with a specific rodent in a given geographic region. Rodent subfamilies associated with hantaviruses include

  • Arvicolinae (Europe)
  • Murinae (Europe and Asia)
  • Sigmodontinae (Americas)

Transmission

Hantavirus is usually transmitted via the inhalation of aerosolized viral antigens or rodent bites. Human to human transmission is seen in American Hantaviruses species (Andes virus).

Incubation period

The incubation period of hantavirus infection is of 9 to 33 days.[1]

Seeding

Following inhalation, the virus replicates in pulmonary macrophages and dendritic cells.

Pathogenesis

The pathogenesis of hantavirus infection can be described by impairment of the barrier function of endothelial cells, fluid extravasation and subsequent organ failure.[2]

Impairment of the barrier function of endothelial cells

  • The primary target cells of hantavirus infection are endothelial cells of capillaries. Most commonly endothelial cells of lungs and heart are involved.
  • Hantaviruses attach to beta-3 integrin receptors of endothelial cells and stimulate T cells.[3][4]
  • Neutralizing antibody (NAbs) are produced as a result of stimulation and beta-3 integrins are inactivated.
  • Inactivation of virus-bound beta-3-integrins contributes to deregulation of vascular endothelial growth factor receptor-2 (VEGFR2) and diminished antagonism of vascular endothelial growth factor (VEGFA).[5]
  • This leads to impairment of vascular endothelial (VE) cadherin expression and subsequent loss of endothelial barrier function.
  • Platelets are consumed in high number in response to the damage to the endothelial layer resulting in thrombocytopenia.

Fluid extravasation

  • Neutralizing antibody (NAbs) also inhibit innate type I interferon (IFN) responses of endothelial cells.
  • This results in inhibition of upregulation of CD73 by IFN-beta on endothelial cells and promotes vascular leakage.

Multiorgan failure

  • Hantaviruses demonstrated to have an immunoreceptor tyrosine-based activation motif (ITAM) on their G1 envelope glycoproteins.
  • Immunoreceptor tyrosine-based activation motif along with local T-cell cytokine production results in cellular downstream and immune cell dysfunction.[6]
  • Attachment of hantavirus to beta-2 integrin receptors on neutrophils also induces the release of neutrophil extracellular traps.
  • Sensitized mononuclear cells infiltrate the lung, myocardial interstitium, and spleen to produce cytokines, particularly TNF-alpha and interferon-gamma, resulting in pulmonary edema and myocarditis

References

  1. ↑ "Incubation Period of Hantavirus Cardiopulmonary Syndrome - Volume 12, Number 8—August 2006 - Emerging Infectious Disease journal - CDC".
  2. ↑ Spiropoulou CF, Srikiatkhachorn A (2013). "The role of endothelial activation in dengue hemorrhagic fever and hantavirus pulmonary syndrome". Virulence. 4 (6): 525–36. doi:10.4161/viru.25569. PMC 5359750. PMID 23841977.
  3. ↑ Gavrilovskaya IN, Shepley M, Shaw R, Ginsberg MH, Mackow ER (1998). "beta3 Integrins mediate the cellular entry of hantaviruses that cause respiratory failure". Proc. Natl. Acad. Sci. U.S.A. 95 (12): 7074–9. PMC 22743. PMID 9618541.
  4. ↑ Gavrilovskaya IN, Peresleni T, Geimonen E, Mackow ER (2002). "Pathogenic hantaviruses selectively inhibit beta3 integrin directed endothelial cell migration". Arch. Virol. 147 (10): 1913–31. doi:10.1007/s00705-002-0852-0. PMID 12376753.
  5. ↑ Geimonen E, Neff S, Raymond T, Kocer SS, Gavrilovskaya IN, Mackow ER (2002). "Pathogenic and nonpathogenic hantaviruses differentially regulate endothelial cell responses". Proc. Natl. Acad. Sci. U.S.A. 99 (21): 13837–42. doi:10.1073/pnas.192298899. PMC 129784. PMID 12368479.
  6. ↑ Mori M, Rothman AL, Kurane I, Montoya JM, Nolte KB, Norman JE, Waite DC, Koster FT, Ennis FA (1999). "High levels of cytokine-producing cells in the lung tissues of patients with fatal hantavirus pulmonary syndrome". J. Infect. Dis. 179 (2): 295–302. doi:10.1086/314597. PMID 9878011.

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