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58-404: Based on the death toll, this outbreak is often referred to as the worst epidemic in the history of Mexico. Subsequent outbreaks continued to baffle both Spanish and native doctors, with little consensus among modern researchers on the pathogenesis . However, recent bacterial genomic studies have suggested that Salmonella , specifically a serotype of Salmonella enterica known as Paratyphi C,

116-549: A 13th-century Norwegian cemetery supports these findings. A young female, who likely died from enteric fever, is proof that the pathogen was present in Europe over 300 years before the epidemics in Mexico. Thus, healthy carriers may have brought the bacteria to the New World, where it thrived. Generations of contact with the strain likely aided those who unknowingly carried the bacteria, as it

174-405: A core of nucleic acid enclosed in a protein coat. Although they are categorized as negative-sense viruses, arenaviruses are ambisense . While sections of their genome encode genes in the negative sense (reverse polarity), other sections encode genes in the opposite (forward/positive sense) direction. This complex gene expression structure is theorized to be a primitive regulatory system, allowing

232-471: A host cell. Genomic sense RNA packaged into the arenavirus virion is designated negative-sense RNA, and must first be copied into a positive-sense mRNA in order to produce viral protein . The RNA segments are denoted Small (S), Medium (M; if present), and Large (L), and code for four viral proteins in a unique ambisense coding strategy. For mammarenaviruses and reptarenaviruses, each RNA segment codes for two viral proteins in opposite orientation such that

290-535: A low cost, taken orally, and able to withstand tropical climates due to the regions where these infections are occurring. For this reason high throughput screening (HTS) of small molecular libraries could be the answer to finding a better remedy. HTS collects libraries of small synthetic molecules that can be used to identify protein promoting "agonist" molecules or protein inhibiting "antagonist" interactions. With HTS sustainable antiviral drugs can be discovered against possible new human pathogenic viruses. Immunotherapy

348-404: A more definitive proposal for the cause of any of the cocoliztli epidemics of 1545–1548 and 1576–1581 awaits further developments in ancient RNA analysis, and the causes of different outbreaks may differ. Beyond the estimations done by Motolinia and others for New Spain, most of the death toll figures cited for the outbreak of 1545–1548 are concerned with Aztec populations. Around 800,000 died in

406-708: A potential risk factor to molecular pathologic signatures of a disease. Thus, the molecular pathological epidemiology paradigm can advance the area of causal inference . Arenavirus An arenavirus is a bi- or trisegmented ambisense RNA virus that is a member of the family Arenaviridae . These viruses infect rodents and occasionally humans. A class of novel, highly divergent arenaviruses, properly known as reptarenaviruses, have also been discovered which infect snakes to produce inclusion body disease , mostly in boa constrictors . At least eight arenaviruses are known to cause human disease. The diseases derived from arenaviruses range in severity. Aseptic meningitis,

464-520: A rare strain of the bacterium Salmonella enterica (subsp. enterica ) which causes paratyphoid fever , suggesting that paratyphoid was the underlying fever behind the disease. The team extracted ancient DNA from the teeth of 29 individuals buried at Teposcolula-Yucundaa in Oaxaca , Mexico. The Contact-era site has the only cemetery to be conclusively linked to victims of the outbreak of 1545–1548. The researchers recognized nonlocal microbial infections using

522-607: A severe human disease that causes inflammation covering the brain and spinal cord, can arise from the lymphocytic choriomeningitis virus . Hemorrhagic fever syndromes, including Lassa fever , are derived from infections such as Guanarito virus , Junin virus , Lassa virus , Lujo virus , Machupo virus , Sabia virus , or Whitewater Arroyo virus . Because of the epidemiological association with rodents, some arenaviruses and bunyaviruses are designated as roboviruses . Viewed in cross-section, arenaviruses contain grainy particles that are ribosomes acquired from their host cells. It

580-534: A sizeable food shortage, affecting the natives and the Spanish colonists. The death of many Aztecs due to the epidemic led to a void in land ownership, with Spanish colonists of all backgrounds looking to exploit these now vacant lands. Coincidentally, the Spanish Emperor, Charles V , had been seeking a way to disempower the encomenderos and establish a more efficient and "ethical" settlement system. Starting around

638-463: A sizeable hemorrhagic fever outbreak could have contributed to the earlier collapse of the Classic Mayan civilization (AD 750–950). However, most experts believe other factors, including climate change, played a larger role. Cocoliztli epidemics usually occurred within two years of a major drought. The epidemic in 1576 occurred after a drought stretching from Venezuela to Canada . Proponents of

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696-406: A small RING-domain containing protein (Z). The Z protein forms homo oligomers and a structural component of the virions. The formation of these oligomers is an essential step for particle assembly and budding. Binding between Z and the viral envelope glycoprotein complex is required for virion infectivity. Z also interacts with the L and NP proteins. Polymerase activity appears to be modulated by

754-671: Is a severe illness with hemorrhagic and neurological manifestations and a case fatality of fifteen to thirty percent. The way this virus spreads is through increased traveling to and from endemic regions. This traveling has led to the importation of Lassa fever into non-endemic metropolitan areas all over the world. A new species of arenavirus named the Lujo virus has been linked to five patients who exhibited symptoms of viral hemorrhagic fever in South Africa. The disease originated near Lusaka, Zambia and spread to Johannesburg , South Africa , after

812-736: Is believed that S. Paratyphi C may have first transferred over to humans from swine in the Old World during or shortly after the Neolithic period. Evolutionary geneticist, María Ávila-Arcos, has questioned this evidence since S. enterica's symptoms are poorly matched with the disease. Ávila-Arcos, Krause’s team, and authors of earlier historical analyses point out that RNA viruses , among other non-bacterial pathogens, have not been investigated. Others have noted that certain symptoms described, including gastrointestinal hemorrhaging, are not present in current observations of S. Paratyphi C infections. Ultimately,

870-403: Is critical for efficient viral RNA synthesis, but potential interterminal double-stranded RNA interactions must be transiently relieved in order to recruit the viral polymerase . The S-segment RNA is approximately 3.5 kb, and encodes the viral nucleocapsid protein (NP) and glycoprotein (GPC). The L-segment RNA is approximately 7.2 kb, and encodes the viral RNA-dependent RNA-polymerase (L) and

928-492: Is critical for recruitment of the viral replication machinery and initiation of viral mRNA transcription and genomic replication . The conserved 5' and 3' RNA termini sequences are complementary and allows each RNA segment to adopt a double-stranded RNA panhandle structure that maintains the termini in close proximity and results in a circular appearance to purified arenavirus genomic templates visualized by electron microscopy . The double-stranded RNA panhandle structure

986-525: Is from this characteristic that they acquired the name arena , from the Latin root meaning sand . The ribosomal structures are not believed to be essential for virus replication. Virus particles, or virions, are pleomorphic (variable in shape) but are often spherical, with a diameter of 60–300 nm, and are covered with surface glycoprotein spikes. The virus contains a beaded nucleocapsid with two single-stranded RNA segments. The nucleocapsid consists of

1044-493: The Valley of Mexico , which led to the widespread abandonment of many Indigenous sites in the area during or shortly after this four-year period. Estimates for the entire number of human lives lost during this epidemic have ranged from 5 to 15 million people, making it one of the most deadly disease outbreaks of all time . The effects of the outbreak extended beyond just a loss in terms of population. The lack of Indigenous labor led to

1102-427: The cocoliztli outbreak, it is significant that all but two of the most common species of domestic mammalian livestock ( llamas and alpacas being the exceptions) come from the Old World. At the same time, droughts plagued Central America, with tree-ring data showing that the outbreak occurred during a megadrought . The lack of water may have worsened sanitation and hygiene. Megadroughts were reported before both

1160-482: The encomenderos , as well as the labor provided by the Indigenous people. This developed into implementing the repartimiento system, which sought to institute a higher level of oversight within the Spanish colonies and maximize the overall tribute extracted for public and crown use. Rules regarding tribute itself were also changed in response to the epidemic of 1545, as fears over future food shortages ran rampant among

1218-766: The house mouse . Old and New World area viruses appear to have diverged ~45,000 years ago. The Old World Mammarenaviruses originated ~23.1-1.88 thousand years ago, most likely in Southern Africa, while the New World Mammarenaviruses evolved in the Latin America-Caribbean region ~41.4-3.3 thousand years ago. The evolution of the Mammarenavirus genus has been studied. The New World and Old World species diverged less than 45,000 years ago. The New World species evolved between 41,400 and 3,300 years ago in

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1276-419: The immune system ( skin tumors and lymphoma after a renal transplant , which requires immunosuppression ), Streptococcus pneumoniae is spread through contact with respiratory secretions , such as saliva , mucus , or cough droplets from an infected person and colonizes the upper respiratory tract and begins to multiply. The pathogenic mechanisms of a disease (or condition) are set in motion by

1334-580: The viral hemorrhagic fever diagnosis, placing increasing interest in the geographic spread of the disease. In 2018, Johannes Krause , an evolutionary geneticist at the Max Planck Institute for the Science of Human History , and colleagues discovered new evidence for an Old World culprit. DNA samples from the teeth of 29 sixteenth-century skeletons in the Oaxaca region of Mexico were identified as belonging to

1392-454: The 1545 and 1576 outbreaks. Additionally, periodic rains during a supposed megadrought, such as those hypothesized for shortly before 1545, would have increased the presence of New World rats and mice. These animals may have carried arenaviruses capable of causing hemorrhagic fevers. The effects of drought and crowded settlements could explain disease transmission, especially if feces spread the pathogen. Scholars suspect cocoliztli emerged in

1450-515: The 19th century. Today, S. Paratyphi C continues to cause enteric fevers and, if untreated, has a mortality rate up to 15%. Infections are primarily limited to developing nations in Africa and Asia, although enteric fevers, in general, are still a health threat worldwide. Infections with S. Paratyphi C are rare, as most cases reported (about 27 million in 2000) resulted from serovars S. Typhi and S. Paratyphi A. The recent discovery of S. Paratyphi C within

1508-599: The Arenavirus infection is related to age, race, or sex within the degree of contact with the dried rodent excreta. All of these diseases pose a great threat to public health in the regions where it is taking place. For example, when the Old World Lassa virus turns into Lassa fever, this usually results in a significant amount of mortality. Similarly the New World Junin virus causes Argentine hemorrhagic fever. This fever

1566-544: The Indians that three out of every four of them perished). Accounts by Toribio de Benavente Motolinia , an early Spanish missionary, seem to contradict Ortiz’s sentiment by suggesting that 60–90% of New Spain 's total population decreased, regardless of ethnicity. However, the modern consensus is that Indigenous people were most affected by cocoliztli , followed by Africans. Europeans experienced lower mortality rates than other groups. One noteworthy European casualty of cocoliztli

1624-546: The Latin America-Caribbean region. The Old World species evolved between 23,100 and 1,880 years ago, most likely in southern Africa. Some arenaviruses are zoonotic pathogens and are generally associated with rodent —transmitted disease in humans. Each virus usually is associated with a particular rodent host species in which it is maintained. Arenaviruses persist in nature by infecting rodents first and then transmitted into humans. Humans can be infected through mucosal exposure to aerosols, or by direct contact of abraded skin with

1682-589: The MEGAN alignment tool (MALT), a program that attempts to match fragments of extracted DNA with a database of bacterial genomes. Within ten individuals, they identified Salmonella enterica subsp. enterica serovar Paratyphi C, which causes enteric fevers in humans. This strain of Salmonella is unique to humans and was not found in any soil samples or pre-contact individuals that were used as controls. Enteric fevers, also known as typhoid or paratyphoid , are similar to typhus and were only distinguished from one another in

1740-460: The Ministries of Health of the two countries in various facets of the outbreak investigation, including laboratory diagnosis, investigations, active case finding and follow-up of contacts. Very few treatment methods are available. The current lack of a licensed vaccine and limited therapeutic options for the arenavirus make it arguably among the most neglected virus groups. The only licensed drug for

1798-463: The Nahuatl word when describing the disease to correspondents in the Old World. In 1970, a historian named Germaine Somolinos d'Ardois looked systematically at the proposed explanations, including hemorrhagic influenza, leptospirosis , malaria , typhus, typhoid , and yellow fever. According to Somolinos d'Ardois, none of these quite matched the 16th-century accounts of cocoliztli , leading him to conclude

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1856-721: The Spanish. By 1577, after years of debate and a second major outbreak of cocoliztli , maize and money were designated as the only two forms of acceptable tribute. Jennifer Scheper Hughes has argued that after decades of minimal success in Mexico, European missionaries were facing a crisis of faith. Indigenous Catholics, in contrast, turned to the Church, finding power, influence, and their own forms of worship. A second large outbreak of cocoliztli occurred in 1576, lasting until about 1580. Although less destructive than its predecessor, causing approximately two million deaths, this outbreak appears in much greater detail in colonial accounts. Many of

1914-597: The association between the L and Z proteins. Interaction between the Z and NP proteins is critical for genome packaging. The glycoprotein (GP) is synthesised as a precursor molecule. It is cleaved into three parts - GP1, GP2 and a stable signal peptide (SSP). These reactions are catalysed by cellular signal peptidases and the cellular enzyme Subtilisin Kexin Isozyme-1 (SKI-1)/Site-1 Protease (S1P). These processes are essential for fusion competence and incorporation of mature GP into nascent budding virion particles. Within

1972-462: The descriptions of cocoliztli symptoms, beyond the bleeding, fevers, and jaundice, were recorded during this epidemic. There are 13 cocoliztli epidemics cited in Spanish accounts between 1545 and 1642, with a later outbreak in 1736 taking a similar form but referred to as tlazahuatl . Pathogenesis In pathology , pathogenesis is the process by which a disease or disorder develops. It can include factors which contribute not only to

2030-464: The disease was a result of a "viral process of hemorrhagic influence." In other words, Somolinos d'Ardois believed cocoliztli was not the result of any known Old World pathogen but possibly a virus of New World origins. There are accounts of similar diseases striking Mexico in pre-Columbian times. The Codex Chimalpopoca states that an outbreak of bloody diarrhea occurred in Colhuacan in 1320. If

2088-632: The disease was indigenous, it was perhaps exacerbated by the worst droughts to affect that region in 500 years and living conditions for Indigenous peoples of Mexico in the wake of the Spanish conquest ( c. 1519). Some historians have suggested cocoliztli was typhus , measles , or smallpox , though the symptoms do not match. Marr and Kiracofe attempted to build off this work by reexamining Hernandez's account of cocoliztli and comparing them with various clinical descriptions of other diseases. They suggested that scholars consider New World arenaviruses and

2146-462: The end of the outbreak in 1549, the encomederos , impacted by the loss in profits resulting and unable to meet the demands of New Spain, were forced to comply with the new tasaciones (regulations). The new ordinances, known as Leyes Nuevas , aimed to limit the amount of tribute encomenderos could demand while also prohibiting them from exercising absolute control over the labor force. Simultaneously, non- encomenderos began claiming lands lost by

2204-681: The family Arenaviridae , arenaviruses were formerly all placed in the genus Arenavirus , but in 2015 were divided into the genera Mammarenavirus for those with mammalian hosts and Reptarenavirus for those infecting snakes. Reptarenaviruses and mammarenavirus are separated by an impenetrable species barrier. Infected rodents cannot pass disease onto snakes, and IBD in captive snakes is not transmissible to humans. A third genus, Hartmanivirus (not to be confused with genus Haartmanvirus of vibrio phages in family Demerecviridae , order Caudovirales ), has also been established, including other species that infect snakes. The organisation of

2262-639: The first patient was transported to a hospital there. The results of genetic sequencing tests conducted by epidemiologists at Columbia University in New York City , USA, and at the Special Pathogens Branch of the Centers for Disease Control in Atlanta , USA, provided evidence that the causative agent of the disease is a virus from the family Arenaviridae, which ultimately resulted in the deaths of four out of

2320-608: The five infected in Zambia and South Africa during the outbreak which began in September 2008. Arenavirus has also pinpointed as the cause of death of three donor organ recipients in Australia who contracted the virus after receiving kidney and a liver donations from a single infected organ donor in late 2006. All three died in the first week of 2007. WHO and its Global Outbreak Alert and Response Network (GOARN) partners continue to support

2378-558: The genome of this genus is typical of arenaviruses but their glycoproteins resemble those of filoviruses . Species in this genus lack the matrix protein. A fourth genus, Antennavirus , has also been established to accommodate two arenaviruses found in striated frogfish ( Antennarius striatus ). A third antennavirus has been detected in Chinook salmon and sockeye salmon . Mammarenaviruses can be divided into two serogroups, which differ genetically and by geographical distribution: When

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2436-464: The infectious material, derived from infected rodents. Aerosols are fine mists or sprays of rodent dried excreta, especially urine that is dropped in the environment. Most of the Arenaviruses caught by humans are within their own homes when these rodents seek shelter. The virus can be caught in factories, from food that has been contaminated, or within agricultural work areas. Humans' risk of contracting

2494-424: The native peoples' health suffered further under the new system. The reducciones brought people and animals in much closer contact with one another. Animals imported from the Old World were potential disease vectors for illnesses. The Aztecs and other Indigenous groups affected by the outbreak were disadvantaged due to their lack of exposure to zoonotic diseases . Given that many Old World pathogens may have caused

2552-476: The negative-sense RNA genome serves as the template for transcription of a single mRNA and the positive-sense copy of the RNA genome templates a second mRNA . The separate coding sequences of the two viral proteins are divided by an intergenic region RNA sequence that is predicted to fold into a stable hairpin structure. The extreme termini of each RNA segment contains a 19 nucleotide highly conserved sequence that

2610-434: The nose, eyes, and mouth. Some also describe spotted skin, gastrointestinal hemorrhaging , leading to bloody diarrhea, and bleeding from the eyes, mouth, and vagina. The onset was rapid and without any precursors that would suggest one was sick . The disease was characterized by an extremely high level of virulence , with death often occurring within a week of the first symptoms, occasionally in as few as 3 or 4 days. Due to

2668-539: The onset of the disease or disorder, but also to its progression and maintenance. The word comes from Ancient Greek πάθος (pathos)  'suffering, disease' and γένεσις (genesis)  'creation'. Types of pathogenesis include microbial infection , inflammation , malignancy and tissue breakdown . For example, bacterial pathogenesis is the process by which bacteria cause infectious illness. Most diseases are caused by multiple processes. For example, certain cancers arise from dysfunction of

2726-415: The outbreak's devastation, but the symptoms do not match any known pathogen. Shortly after 1548, the Spanish started calling the disease tabardillo (typhus), which the Spanish had recognized since the late 15th century. However, the symptoms of cocoliztli were still not identical to the typhus or spotted fever observed in the Old World. Francisco Hernández de Toledo , a Spanish physician, insisted on using

2784-441: The role these pathogens may have played in colonial disease outbreaks. Marr and Kiracofe theorized that arenaviruses , mainly affecting rodents, were not prominent in the pre-Columbian Americas. Consequently, rat and mice infestations brought upon by the arrival of the Spanish may have, combined with climatic and landscape change, brought these arenaviruses into much closer contact with people. Some subsequent research has focused on

2842-431: The southern and central Mexico Highlands, near modern-day Puebla City . Shortly after its initial onset, however, it may have spread as far north as Sinaloa and as south as Chiapas and Guatemala , where it was called gucumatz . It may have spread to South America to Ecuador and Peru , although it is hard to be certain that the same disease was described. The outbreak seemed to be limited to higher elevations, as it

2900-427: The treatment of human arenavirus infection is the nucleoside analogue ribavirin . Ribavirin reduces morbidity and mortality in humans infected with certain arenaviruses, such as LASV and JUNV infections, if it is taken in the early stages of the disease. Ribavirin displays mixed success in treating severe arenaviral disease and is associated with significant toxicities. Effective antiviral drugs need to be produced at

2958-503: The underlying causes, which if controlled would allow the disease to be prevented . Often, a potential cause is identified by epidemiological observations before a pathological link can be drawn between the cause and the disease. The pathological perspective can be directly integrated into an epidemiological approach in the interdisciplinary field of molecular pathological epidemiology . Molecular pathological epidemiology can help to assess pathogenesis and causality by means of linking

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3016-470: The viral theory of cocoliztli suggest the relationship between drought and outbreak may reflect increased numbers of rodents carrying viral hemorrhagic fever during the rains that followed the drought. Cocoliztli seemed to preferentially, but not exclusively, target native people. Gonzalo de Ortiz, an encomendero , wrote "envió Dios tal enfermedad sobre ellos que de quarto partes de indios que avia se llevó las tres" (God sent down such sickness upon

3074-399: The virulence and effectiveness of the disease, recognizing its existence in the archaeological record has been difficult. This is because cocoliztli , and other diseases that work rapidly, usually do not leave impacts (lesions) on the decedent's bones, despite causing significant damage to the gastrointestinal , respiratory , and other bodily systems. Numerous 16th-century accounts detail

3132-589: The virus is classified "Old World" this means it was found in the Eastern Hemisphere in places such as Europe, Asia, and Africa. When it is found in the Western Hemisphere, in places such as Argentina, Bolivia, Venezuela, Brazil, and the United States, it is classified "New World". Lymphocytic choriomeningitis (LCM) virus is the only mammarenavirus found worldwide because of its ubiquitous Old World host,

3190-411: The virus to control what proteins are synthesized at what point in the life cycle. The life cycle of the arenavirus is restricted to the cell cytoplasm. Arenaviruses have a segmented RNA genome that consists of two single-stranded ambisense RNAs. As with all negative-sense RNA viruses, the genomic RNA alone is not infectious and the viral replication machinery is required to initiate infection within

3248-715: Was Bernardino de Sahagún , a Spanish clergyman and author of the Florentine Codex , who contracted the disease in 1546. Sahagún suffered cocoliztli a second time in 1590 and subsequently died. The social and physical environment of Colonial Mexico was likely key in allowing the outbreak of 1545–1548 to reach the heights that it did. Following the conquest, the Spanish colonists forced the Aztecs and other Indigenous peoples onto easily governable reducciones (congregations) that focused on agricultural production and conversion to Christianity. Weakened by war and chronic disease outbreaks,

3306-484: Was at least partially responsible for this initial outbreak. Others believe cocoliztli was caused by an indigenous viral hemorrhagic fever , perhaps exacerbated by the worst droughts to affect that region in 500 years and poor living conditions for Indigenous peoples of Mexico following the Spanish conquest ( c. 1519). At least 12 epidemics are attributed to cocoliztli , with the largest occurring in 1545, 1576, 1736, and 1813. Soto et al. have hypothesized that

3364-676: Was nearly absent from coastal regions at sea level, e.g., the plains along the Gulf of Mexico and Pacific coast . Although symptomatic descriptions of cocoliztli are similar to those of Old World diseases, including measles , yellow fever , and typhus , many researchers recognize it as a separate disease. According to Francisco Hernández de Toledo , a physician who witnessed the outbreak in 1576, symptoms included high fever, severe headache, vertigo , black tongue, dark urine, dysentery , severe abdominal and chest pain, head and neck nodules, neurological disorders, jaundice , and profuse bleeding from

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