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{{Lassa fever}}
{{Lassa fever}}
{{CMG}}; {{AE}} {{Ammu}}
{{CMG}}; {{AE}} {{Ammu}}
==Overview==
Lassa fever may be transmitted from either infected animals (typically rodents) or humans following exposure to body fluids and excretions/secretions from the respiratory tract or GI tract. Following transmission, Lassa virus infects the endothelium and replicates intracellularly using an L-polymerase enzyme and nucleocapsid protein NP, which synthesize ribonucleoprotein (RNP) that produces mRNA and antigenomic RNA required for transcription. NP protein helps the virus evade the host immune system. Following transcription, vascular dysfunction ensues, resulting in the development of clinical manifestations of the disease. Although all organs may potentially be infected, the liver is a common target organ, and hepatitis/hepatic necrosis is typical following Lassa fever infection.
==Transmission==
===Animal to Human===
* Infection in humans typically occurs via exposure to animal (typically rodent) [[excretion|excrement]] through the [[respiratory tract|respiratory]] or [[gastrointestinal tract|gastrointestinal]] tracts.
* [[Inhalation]] of tiny particles of infected aerosol is thought to be the most significant means of exposure, but transmission through direct exposure of infection to skin wounds or mucous membranes.
* Handling of dead infected animals has also been associated with the transmission of Lassa virus.
===Human to Human===
* Lassa virus may be transmitted following exposure to [[blood]], [[tissue]], [[secretion]]s (including breast milk), or [[excretion]]s of an infected individual.
* The virus cannot be transmitted without the exchange of [[body fluids]].
==Cellular Pathogenesis==
===Host Cell Entry===
* Following transmission, Lassa virus primarily infects the [[endothelial cells]].
* The [[Lassa virus]] gains entry into the host cell by means of the [[cell-surface receptor]] the alpha-[[dystroglycan]] (alpha-DG),<ref name="pmid10888638">{{cite journal| author=Bowen MD, Rollin PE, Ksiazek TG, Hustad HL, Bausch DG, Demby AH et al.| title=Genetic diversity among Lassa virus strains. | journal=J Virol | year= 2000 | volume= 74 | issue= 15 | pages= 6992-7004 | pmid=10888638 | doi= | pmc=PMC112216 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10888638  }} </ref> a versatile [[receptor]] for [[protein]]s of the [[extracellular matrix]].
* Unlike most enveloped viruses which use [[clathrin]]-coated pits for cellular entry and bind to their [[receptors]] in a pH dependent fashion, Lassa virus instead undergoes cellular entry via endocytosis using alpha-dystroglycan receptor (ubiquitously expressed cell surface receptor), independent of either [[clathrin]], [[caveolin]], [[dynamin]] or [[actin]].
*Once within the [[cell]], the [[viruses]] are rapidly delivered to [[endosomes]] via vesicular trafficking. Once in contact with the [[endosome]], Lassa virus evades endosomal degradation using envelope glycoproteins, which mediate a pH-dependent binding and [[membrane fusion]].
===RNA Synthesis===
*Intracellular RNA synthesis is initiated within an L-polymerase enzyme, which utilizes viral RNA templates and nucleocapsid protein NP to synthesize viral ribonucleoprotein (RNP). Once synthesized, RNP is transmitted to the host cell cytoplasm, and transcription of mRNA and antigenomic RNA (agRNA).<ref name="pmid23202452">{{cite journal| author=Yun NE, Walker DH| title=Pathogenesis of Lassa fever. | journal=Viruses | year= 2012 | volume= 4 | issue= 10 | pages= 2031-48 | pmid=23202452 | doi=10.3390/v4102031 | pmc=PMC3497040 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23202452  }}</ref>
===Host Immune Response===
*Lassa fever evades the host immune system by production of NP protein, which has an exonuclease activity and causes the inhibition of host type I IFN signaling.<ref name="pmid16940530">{{cite journal| author=Martínez-Sobrido L, Zúñiga EI, Rosario D, García-Sastre A, de la Torre JC| title=Inhibition of the type I interferon response by the nucleoprotein of the prototypic arenavirus lymphocytic choriomeningitis virus. | journal=J Virol | year= 2006 | volume= 80 | issue= 18 | pages= 9192-9 | pmid=16940530 | doi=10.1128/JVI.00555-06 | pmc=PMC1563941 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16940530  }} </ref>
*Endothelial dysfunction results in the release of pro-inflammatory cytokines and cell mediators<ref name="pmid23202452">{{cite journal| author=Yun NE, Walker DH| title=Pathogenesis of Lassa fever. | journal=Viruses | year= 2012 | volume= 4 | issue= 10 | pages= 2031-48 | pmid=23202452 | doi=10.3390/v4102031 | pmc=PMC3497040 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23202452  }} </ref>, which in turn cause [[platelet]] dysfunction, hepatic necrosis, suppression of cardiac function, and development of Lassa fever-associated clinical manifestations, including facial edema, pleural and pericardial effusions, and hypovolemic shock.
*Lassa fever may potentially infect all organs, but the liver and auditory sensorineural system are commonly involved.
*Failure of the host to mount an adequate cellular [[immune response]] to control viral dissemination, along with disseminated replication in [[tissues]] and absence of neutralizing [[antibodies]], results in host death.<ref name="pmid20360949">{{cite journal| author=Flatz L, Rieger T, Merkler D, Bergthaler A, Regen T, Schedensack M et al.| title=T cell-dependence of Lassa fever pathogenesis. | journal=PLoS Pathog | year= 2010 | volume= 6 | issue= 3 | pages= e1000836 | pmid=20360949 | doi=10.1371/journal.ppat.1000836 | pmc=PMC2847900 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20360949  }} </ref> Prompt host immune response is critical for host survival, and fatal Lassa fever is often characterized by impaired or delayed [[cellular immunity]]<ref name="CDC">{{cite web | title = The Centers for Disease Control and Prevention | url =http://www.cdc.gov/vhf/lassa/transmission/index.html }}</ref>.


{{SK}} Lassa hemorrhagic fever; LHF
==Genetics==
==Overview==
*Replication for [[Lassa virus]] is very rapid and demonstrates a temporal control.<ref name="pmid16629503">{{cite journal| author=Lashley FR| title=Emerging infectious diseases at the beginning of the 21st century. | journal=Online J Issues Nurs | year= 2006 | volume= 11 | issue= 1 | pages= 2 | pmid=16629503 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16629503 }} </ref>  
Lassa fever is a zoonotic disease caused by Lassa virus and spread by multimammate rat vector. It is spread through person-to-person contact, direct contact with rodent excretion and after an [[incubation period]] of 1-24 days can manifest as [[fever]], [[muscle aches]], [[sore throat]], [[nausea]], [[vomiting]], chest and [[abdominal pain]], [[weakness]], [[cough]], [[headache]], exudative [[pharyngitis]], [[anemia]], low [[blood pressure]], and [[diarrhea]].
*The initial replication step is transcription of [[mRNA]] copies of the negative (minus-sense) genome. This process ensures an adequate supply of viral proteins for subsequent steps of replication, as the NP and L proteins are translated from the [[mRNA]].
==Pathophysiology==
*Following the initial replication step, the positive (plus-sense) [[genome]] then synthesizes viral complementary [[RNA]] (vcRNA) copies of itself. The vcRNA copies are then used to synthesize more mRNA and to serve as templates for the production of more negative-sense progeny. The [[mRNA]] synthesized from [[vcRNA]] are then translated to produce GP and Z proteins.  
The current case definition for suspecting Lassa fever is as follows.<ref name=Prevention>{{cite web | title = The Centers for Disease Control and Prevention | url =http://www.cdc.gov/vhf/abroad/pdf/african-healthcare-setting-vhf.pdf }}</ref>.
*This temporal control allows the spike proteins to be produced last, and therefore, delay recognition by the host [[immune system]].
{|
|-
| valign=top |
{| style="border: 0px; font-size: 90%; margin: 3px; width: 500px;" align=center
! style="padding: 0 5px; font-size: 100%; background: #4479BA" align=center | ''{{fontcolor|#FFF|Unexplained fever at least 38oC or 100.4oF for one week or more}}''
|-
! style="padding: 0 5px; font-size: 95%; background:  #DCDCDC" align=left | '''And 1 of the following:'''
|-
| rowspan="1" style="font-size: 95%; padding: 0 5px; background: #F5F5F5" | ▸ No response to standard treatment for most likely cause of [[fever]] ([[malaria]], [[typhoid fever]])  the choice of regimen.
|-
| rowspan="1" style="font-size: 95%; padding: 0 5px; background: #F5F5F5" | ▸ Readmitted within 3 weeks of inpatient care for an illness with [[fever]].
|-
! style="padding: 0 5px; font-size: 95%; background: #DCDCDC" align=left | '''And 1 of the following'''
|-
| rowspan="1" style="font-size: 95%; padding: 0 5px; background: #F5F5F5" | ▸ [[Edema]] or [[bleeding]].
|-
| rowspan="1" style="font-size: 95%; padding: 0 5px; background: #F5F5F5" | ▸ [[Sore throat]] and [[retrosternal pain]]/[[vomiting]].
|-
| rowspan="1" style="font-size: 95%; padding: 0 5px; background: #F5F5F5" | ▸ Spontaneous [[abortion]] following [[fever]].
|-
| rowspan="1" style="font-size: 95%; padding: 0 5px; background: #F5F5F5" | ▸ [[Hearing loss]] following [[fever]].
<small>
|}
|}
===Pathogenesis===
* Lassa virus infects the [[endothelial cells]] and perturbation of [[vascular function]] is likely to be central to Lassa fever-associated [[pathobiology]], since the signs of increased [[vascular permeability]], such as [[facial edema]] and [[pleural]] and [[pericardial effusions]], indicate a poor [[prognosis]] for the [[disease]] outcome.
* Failure to develop the cellular [[immune response]] that would control dissemination of LASV, which is indicated by high serum [[virus]] titers, combined with disseminated replication in [[tissues]] and absence of neutralizing [[antibodies]], leads to the development of fatal [[Lassa fever]].<ref name="pmid20360949">{{cite journal| author=Flatz L, Rieger T, Merkler D, Bergthaler A, Regen T, Schedensack M et al.| title=T cell-dependence of Lassa fever pathogenesis. | journal=PLoS Pathog | year= 2010 | volume= 6 | issue= 3 | pages= e1000836 | pmid=20360949 | doi=10.1371/journal.ppat.1000836 | pmc=PMC2847900 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20360949 }} </ref>
* Some of the characteristic symptoms of the virus include: [[fever]], [[muscle aches]], [[sore throat]], [[nausea]], [[vomiting]], chest and [[abdominal pain]], [[weakness]], [[cough]], [[headache]], [[exudative pharyngitis]], [[anemia]], low [[blood pressure]], and [[diarrhea]]. Because its symptoms are similar to other febrile illness found in Africa, Lassa virus is hard to diagnose. It can eventually can cause [[pulmonary edema]], [[pleural]] and [[pericardial effusion]], [[facial edema]], [[bleeding]] from mucosal surfaces, neurological complications, [[deafness]], [[lymphocytopenia]], [[thrombocytopenia]], and [[ascites]]. Often [[sore throat]], [[vomiting]], and [[bleeding]] are associated with higher fatality. There are four clinical stages of Lassa fever. The first stages occurs within the first three days and its symptoms include a high fever, weakness, and a general depression in activity. The second stage transpires from day 4 to day 7 where the patient experiences some of the more common/characteristic symptoms as stated above. The third stage begins at the seventh day and includes more severe symptoms such as: facial edema, convulsions, mucosal bleeding, internal bleeding, and disorientation. The fourth stage usually occurs after the 14th day and ends in coma and death.
* Only 20% of people who contract Lassa fever have severe multisystem trauma, meaning that 80% of people have only the milder symptoms. It has also been found that most cases of Lassa fever occur as the seasons change from dry to wet.


===Transmission===
==Gross Pathology==
[[File:LassaBoy.png|thumb|center|400 px|Lassa Fever wikipedia.png<SMALL><SMALL>''[http://en.wikipedia.org/wiki/Lassa_fever]''<ref name="CDC">{{Cite web | title =wikipedia  | url = http://en.wikipedia.org/wiki/Lassa_fever}}</ref></SMALL></SMALL>]]
Lassa virus commonly involves the liver and results in [[hepatocellular necrosis]] and [[apoptosis]].  
====Rodent to Human====
Other organs may be involved, and Lassa fever infection may manifest with the following:<ref name="pmid4246571">{{cite journal| author=Frame JD, Baldwin JM, Gocke DJ, Troup JM| title=Lassa fever, a new virus disease of man from West Africa. I. Clinical description and pathological findings. | journal=Am J Trop Med Hyg | year= 1970 | volume= 19 | issue= 4 | pages= 670-6 | pmid=4246571 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=4246571  }} </ref><ref name="pmid7081389">{{cite journal| author=Walker DH, McCormick JB, Johnson KM, Webb PA, Komba-Kono G, Elliott LH et al.| title=Pathologic and virologic study of fatal Lassa fever in man. | journal=Am J Pathol | year= 1982 | volume= 107 | issue= 3 | pages= 349-56 | pmid=7081389 | doi= | pmc=PMC1916239 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7081389  }} </ref><ref name="pmid3953952">{{cite journal| author=McCormick JB, Walker DH, King IJ, Webb PA, Elliott LH, Whitfield SG et al.| title=Lassa virus hepatitis: a study of fatal Lassa fever in humans. | journal=Am J Trop Med Hyg | year= 1986 | volume= 35 | issue= 2 | pages= 401-7 | pmid=3953952 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3953952  }} </ref>
* Infection in humans typically occurs via exposure to animal [[excretion|excrement]] through the [[respiratory tract|respiratory]] or [[gastrointestinal tract|gastrointestinal]] tracts.  
* [[Inhalation]] of tiny particles of infective material ([[aerosol]]) is believed to be the most significant means of exposure.  
* It is possible to acquire the [[infection]] through broken [[skin]] or [[mucous membrane]]s that are directly exposed to infective material. In fatal cases, Lassa fever is characterized by impaired or delayed [[cellular immunity]] leading to [[fulminant]] [[viremia]]<ref name=CDC>{{cite web | title = The Centers for Disease Control and Prevention | url =http://www.cdc.gov/vhf/lassa/transmission/index.html }}</ref>.
* Finally, because Mastomys rodents are sometimes consumed as a food source, [[infection]] may occur via direct contact when they are caught and prepared for food.


====Human to Human====
*[[Splenic necrosis]]
* There are a number of ways in which the [[virus]] may be transmitted, or spread, to [[humans]].
*[[Adrenocortical necrosis]]
* This type of transmission occurs when a person comes into contact with virus in the [[blood]], [[tissue]], [[secretion]]s, or [[excretion]]s of an individual infected with the Lassa virus.
*Mononuclear [[interstitial myocarditis]]
* The virus cannot be spread through casual contact (including skin-to-skin contact without exchange of [[body fluids]]).
*Pulmonary [[alveolar edema]] with capillary congestion and mild [[interstitial pneumonitis]]
* Person-to-person transmission is common in both village and health care settings, where, along with the above-mentioned modes of transmission, the virus also may be spread in contaminated medical equipment, such as reused needles (this is called [[nosocomial]] [[transmission]]). Frequency of transmission via sexual contact has not been established. * Transmission through [[breast milk]] has also been observed.
*Lymph nodal sinus [[histiocytosis]]
===Molecular Pathology===
*Gastrointestinal mucosal [[petechiae]]
* Lassa virus infect the cells especially endothelial cells and release cytokines and other inflammatory cell mediators.<ref name="pmid23202452">{{cite journal| author=Yun NE, Walker DH| title=Pathogenesis of Lassa fever. | journal=Viruses | year= 2012 | volume= 4 | issue= 10 | pages= 2031-48 | pmid=23202452 | doi=10.3390/v4102031 | pmc=PMC3497040 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23202452  }} </ref>
*[[Renal tubular injury]]
* The mediators cause [[platelet]] dysfunction and  suppress [[cardiac function]] as well as produce clinical manifestation of [[shock]] and [[inflammation]].
*[[Interstitial nephritis]]
* Microscopically, the [[virus]] causes [[hepatocellular necrosis]] and capillary lesions that can cause certain [[organs]] to [[hemorrhage]]. Lassa virus travels through the [[body]] via the [[blood]], [[lymph vessels]], [[respiratory tract]], and [[digestive tract]]. Because of the multitude of dissemination strategies in the [[body]], it is able to [[infect]] almost every [[organ]] in the human [[body]]. It has even been found in the [[cerebrospinal fluid]] which suggests a [[malfunction]] or defect of the [[blood brain barrier]]. Even though the [[virus]] targets the entire [[body]], the [[liver]] is usually the [[organ]] that is most affected. The [[virus]] escapes detection by suppressing the [[immune system]].
* Patients infected with LASV produce IgM and IgG antibody isotypes.<ref name="pmid3805773">{{cite journal| author=Johnson KM, McCormick JB, Webb PA, Smith ES, Elliott LH, King IJ| title=Clinical virology of Lassa fever in hospitalized patients. | journal=J Infect Dis | year= 1987 | volume= 155 | issue= 3 | pages= 456-64 | pmid=3805773 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3805773  }} </ref>.
* Microscopic findings include [[hepatocellular necrosis]] and [[apoptosis]], [[splenic necrosis]], [[adrenocortical necrosis]], mild mononuclear [[interstitial myocarditis]] without myocardial fiber [[necrosis]], [[alveolar edema]] with capillary congestion and mild [[interstitial pneumonitis]], lymph nodal sinus [[histiocytosis]] with [[mitoses]], gastrointestinal mucosal [[petechiae]], [[renal tubular injury]], and [[interstitial nephritis]].<ref name="pmid4246571">{{cite journal| author=Frame JD, Baldwin JM, Gocke DJ, Troup JM| title=Lassa fever, a new virus disease of man from West Africa. I. Clinical description and pathological findings. | journal=Am J Trop Med Hyg | year= 1970 | volume= 19 | issue= 4 | pages= 670-6 | pmid=4246571 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=4246571  }} </ref><ref name="pmid7081389">{{cite journal| author=Walker DH, McCormick JB, Johnson KM, Webb PA, Komba-Kono G, Elliott LH et al.| title=Pathologic and virologic study of fatal Lassa fever in man. | journal=Am J Pathol | year= 1982 | volume= 107 | issue= 3 | pages= 349-56 | pmid=7081389 | doi= | pmc=PMC1916239 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7081389  }} </ref><ref name="pmid3953952">{{cite journal| author=McCormick JB, Walker DH, King IJ, Webb PA, Elliott LH, Whitfield SG et al.| title=Lassa virus hepatitis: a study of fatal Lassa fever in humans. | journal=Am J Trop Med Hyg | year= 1986 | volume= 35 | issue= 2 | pages= 401-7 | pmid=3953952 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3953952  }} </ref>
* The necrotic [[hepatocytes]] were randomly distributed often forming foci of contiguous [[cells]]. Mononuclear [[phagocytes]] were observed either contacting or phagocytosing necrotic [[hepatocytes]].
* [[Splenic necrosis]] was found in the marginal zone of the [[periarteriolar lymphocytic sheath]]. [[Splenic venous subendothelium]] appeared to be infiltrated by [[lymphocytes]] and other [[mononuclear cells]].


==Microscopic Pathology==
==Microscopic Pathology==
The images below display key features of the Lassa virus.
Typical features of Lassa fever-associated hepatitis include the following:
*Acidophilic necrosis
*Apoptotic changes
*Ballooning degeneration
*Pycnotic nuclei
*Microvascular changes
*Councilman bodies (intracellular inclusion bodies)
 
The images below display key features of microscopic pathology of Lassa virus.
<gallery>
<gallery>
Image:PHIL 2994 lores.jpg|This photomicrograph shows hepatitis caused by the Lassa virus, using toluidine-blue azure II stain. Source: CDC microbiologist Dr. W. Winn.<SMALL><SMALL>''[http://phil.cdc.gov/phil/details.asp  Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.]''<ref name="PHIL">{{Cite web | title = Public Health Image Library (PHIL), Centers for Disease Control and Prevention | url = http://phil.cdc.gov/phil/details.asp/}}</ref></SMALL></SMALL>
Image:PHIL 2994 lores.jpg|This photomicrograph demonstrates hepatitis caused by the Lassa virus, using toluidine-blue azure II stain. Retrieved from the Public Health Image Library (PHIL) of the Centers for Disease Control and Prevention.<SMALL><SMALL>''[http://phil.cdc.gov/phil/details.asp  Retrieved from the Public Health Image Library (PHIL), Centers for Disease Control and Prevention.]''<ref name="PHIL">{{Cite web | title = Public Health Image Library (PHIL), Centers for Disease Control and Prevention | url = http://phil.cdc.gov/phil/details.asp/}}</ref></SMALL></SMALL>
Image:Ebola virus1.png|This transmission electron micrograph (TEM) demonstrates the ultrastructural morphologic changes in this tissue sample isolate.<SMALL><SMALL>''[http://phil.cdc.gov/phil/details.asp  Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.]''<ref name="PHIL">{{Cite web | title = Public Health Image Library (PHIL), Centers for Disease Control and Prevention | url = http://phil.cdc.gov/phil/details.asp/}}</ref></SMALL></SMALL>
Image:Patho 01 lassa.jpg|This transmission electron micrograph (TEM) demonstrates the cytoarchitectural changes of a liver tissue specimen extracted from a patient with Lassa fever. The presence of a typical Councilman body, pycnotic nuclei in an area of acidophilic necrosis, and microvacuolar fatty changes are noted.<SMALL><SMALL>''[http://phil.cdc.gov/phil/details.asp  Retrieved from the Public Health Image Library (PHIL), Centers for Disease Control and Prevention.]''<ref name="PHIL">{{Cite web | title = Public Health Image Library (PHIL), Centers for Disease Control and Prevention | url = http://phil.cdc.gov/phil/details.asp/}}</ref></SMALL></SMALL>
Image:Ebola virus3.png|Scanning electron micrograph (SEM) revealing ultrastructural morphologic features of the Ebola virus from the Ivory Coast of Africa.<SMALL><SMALL>''[http://phil.cdc.gov/phil/  Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.]''<ref name="PHIL">{{Cite web | title = Public Health Image Library (PHIL), Centers for Disease Control and Prevention | url = http://phil.cdc.gov/phil/}}</ref></SMALL></SMALL>
Image:Lassa patho 02.jpg|Scanning electron micrograph (SEM) demonstrates the cytoarchitectural changes of a liver tissue specimen extracted from a patient with Lassa fever.  A zone of acidophilic necrosis, and numbers of pycnotic nuclei are noted.<SMALL><SMALL>''[http://phil.cdc.gov/phil/details.asp Retrieved from the Public Health Image Library (PHIL), Centers for Disease Control and Prevention.]''<ref name="PHIL">{{Cite web | title = Public Health Image Library (PHIL), Centers for Disease Control and Prevention | url = http://phil.cdc.gov/phil/details.asp}}</ref></SMALL></SMALL>
Image:Ebola virus4.png|Negatively-stained transmission electron micrograph (TEM) demonstrating the ultrastructural curvilinear morphologic features displayed by the Ebola virus from the Ivory Coast of Africa.<SMALL><SMALL>''[http://phil.cdc.gov/phil/  Adapted from Public Health Image Library (PHIL), Centers for Disease Control and Prevention.]''<ref name="PHIL">{{Cite web | title = Public Health Image Library (PHIL), Centers for Disease Control and Prevention | url = http://phil.cdc.gov/phil/}}</ref></SMALL></SMALL></gallery>
Image:Lassa patho 03.jpg|Sudan III-stained photomicrograph demonstrates the cytoarchitectural changes of a liver tissue specimen extracted from a patient with Lassa fever. Microvacuolar fatty necrosis is noted.<SMALL><SMALL>''[http://phil.cdc.gov/phil/details.asp  Retrieved from the Public Health Image Library (PHIL), Centers for Disease Control and Prevention.]''<ref name="PHIL">{{Cite web | title = Public Health Image Library (PHIL), Centers for Disease Control and Prevention | url = http://phil.cdc.gov/phil/details.asp}}</ref></SMALL></SMALL>
Image:Lassa patho 04.jpg|This photomicrograph demonstrates hepatitis caused by the Lassa virus, using toluidine-blue azure II stain, magnified 500X.<SMALL><SMALL>''[http://phil.cdc.gov/phil/details.asp Retrieved from the Public Health Image Library (PHIL), Centers for Disease Control and Prevention.]''<ref name="PHIL">{{Cite web | title = Public Health Image Library (PHIL), Centers for Disease Control and Prevention | url = http://phil.cdc.gov/phil/details.asp/}}</ref></SMALL></SMALL></gallery>


==References==
==References==
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[[Category:Tropical disease]]
[[Category:Tropical disease]]
[[Category:Biological weapons]]
[[Category:Biological weapons]]
[[Category:Infectious disease]]

Latest revision as of 18:09, 18 September 2017

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

Overview

Lassa fever may be transmitted from either infected animals (typically rodents) or humans following exposure to body fluids and excretions/secretions from the respiratory tract or GI tract. Following transmission, Lassa virus infects the endothelium and replicates intracellularly using an L-polymerase enzyme and nucleocapsid protein NP, which synthesize ribonucleoprotein (RNP) that produces mRNA and antigenomic RNA required for transcription. NP protein helps the virus evade the host immune system. Following transcription, vascular dysfunction ensues, resulting in the development of clinical manifestations of the disease. Although all organs may potentially be infected, the liver is a common target organ, and hepatitis/hepatic necrosis is typical following Lassa fever infection.

Transmission

Animal to Human

  • Infection in humans typically occurs via exposure to animal (typically rodent) excrement through the respiratory or gastrointestinal tracts.
  • Inhalation of tiny particles of infected aerosol is thought to be the most significant means of exposure, but transmission through direct exposure of infection to skin wounds or mucous membranes.
  • Handling of dead infected animals has also been associated with the transmission of Lassa virus.

Human to Human

  • Lassa virus may be transmitted following exposure to blood, tissue, secretions (including breast milk), or excretions of an infected individual.
  • The virus cannot be transmitted without the exchange of body fluids.

Cellular Pathogenesis

Host Cell Entry

RNA Synthesis

  • Intracellular RNA synthesis is initiated within an L-polymerase enzyme, which utilizes viral RNA templates and nucleocapsid protein NP to synthesize viral ribonucleoprotein (RNP). Once synthesized, RNP is transmitted to the host cell cytoplasm, and transcription of mRNA and antigenomic RNA (agRNA).[2]

Host Immune Response

  • Lassa fever evades the host immune system by production of NP protein, which has an exonuclease activity and causes the inhibition of host type I IFN signaling.[3]
  • Endothelial dysfunction results in the release of pro-inflammatory cytokines and cell mediators[2], which in turn cause platelet dysfunction, hepatic necrosis, suppression of cardiac function, and development of Lassa fever-associated clinical manifestations, including facial edema, pleural and pericardial effusions, and hypovolemic shock.
  • Lassa fever may potentially infect all organs, but the liver and auditory sensorineural system are commonly involved.
  • Failure of the host to mount an adequate cellular immune response to control viral dissemination, along with disseminated replication in tissues and absence of neutralizing antibodies, results in host death.[4] Prompt host immune response is critical for host survival, and fatal Lassa fever is often characterized by impaired or delayed cellular immunity[5].

Genetics

  • Replication for Lassa virus is very rapid and demonstrates a temporal control.[6]
  • The initial replication step is transcription of mRNA copies of the negative (minus-sense) genome. This process ensures an adequate supply of viral proteins for subsequent steps of replication, as the NP and L proteins are translated from the mRNA.
  • Following the initial replication step, the positive (plus-sense) genome then synthesizes viral complementary RNA (vcRNA) copies of itself. The vcRNA copies are then used to synthesize more mRNA and to serve as templates for the production of more negative-sense progeny. The mRNA synthesized from vcRNA are then translated to produce GP and Z proteins.
  • This temporal control allows the spike proteins to be produced last, and therefore, delay recognition by the host immune system.

Gross Pathology

Lassa virus commonly involves the liver and results in hepatocellular necrosis and apoptosis. Other organs may be involved, and Lassa fever infection may manifest with the following:[7][8][9]

Microscopic Pathology

Typical features of Lassa fever-associated hepatitis include the following:

  • Acidophilic necrosis
  • Apoptotic changes
  • Ballooning degeneration
  • Pycnotic nuclei
  • Microvascular changes
  • Councilman bodies (intracellular inclusion bodies)

The images below display key features of microscopic pathology of Lassa virus.

References

  1. ↑ Bowen MD, Rollin PE, Ksiazek TG, Hustad HL, Bausch DG, Demby AH; et al. (2000). "Genetic diversity among Lassa virus strains". J Virol. 74 (15): 6992–7004. PMC 112216. PMID 10888638.
  2. ↑ 2.0 2.1 Yun NE, Walker DH (2012). "Pathogenesis of Lassa fever". Viruses. 4 (10): 2031–48. doi:10.3390/v4102031. PMC 3497040. PMID 23202452.
  3. ↑ Martínez-Sobrido L, Zúñiga EI, Rosario D, García-Sastre A, de la Torre JC (2006). "Inhibition of the type I interferon response by the nucleoprotein of the prototypic arenavirus lymphocytic choriomeningitis virus". J Virol. 80 (18): 9192–9. doi:10.1128/JVI.00555-06. PMC 1563941. PMID 16940530.
  4. ↑ Flatz L, Rieger T, Merkler D, Bergthaler A, Regen T, Schedensack M; et al. (2010). "T cell-dependence of Lassa fever pathogenesis". PLoS Pathog. 6 (3): e1000836. doi:10.1371/journal.ppat.1000836. PMC 2847900. PMID 20360949.
  5. ↑ "The Centers for Disease Control and Prevention".
  6. ↑ Lashley FR (2006). "Emerging infectious diseases at the beginning of the 21st century". Online J Issues Nurs. 11 (1): 2. PMID 16629503.
  7. ↑ Frame JD, Baldwin JM, Gocke DJ, Troup JM (1970). "Lassa fever, a new virus disease of man from West Africa. I. Clinical description and pathological findings". Am J Trop Med Hyg. 19 (4): 670–6. PMID 4246571.
  8. ↑ Walker DH, McCormick JB, Johnson KM, Webb PA, Komba-Kono G, Elliott LH; et al. (1982). "Pathologic and virologic study of fatal Lassa fever in man". Am J Pathol. 107 (3): 349–56. PMC 1916239. PMID 7081389.
  9. ↑ McCormick JB, Walker DH, King IJ, Webb PA, Elliott LH, Whitfield SG; et al. (1986). "Lassa virus hepatitis: a study of fatal Lassa fever in humans". Am J Trop Med Hyg. 35 (2): 401–7. PMID 3953952.
  10. ↑ 10.0 10.1 10.2 10.3 10.4 "Public Health Image Library (PHIL), Centers for Disease Control and Prevention".

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