6. SIATL, Simulador de Flujos de Agua de Cuencas Hidrográficas Versión 2.2
7.1 Ejercicio 1 Análisis de una cuenca vinculado a un evento de tormenta para evaluar el caudal pico
Collectively, these events allow for an early response that is not only mediated by early proinflammatory mediators to occur but for early shaping of a long-‐term adaptive response. As the development of a Th1 versus a Th2 response leads to development of specific adaptive re-‐ sponses and different pathological outcomes when disregulated, it is important to look at the Th1/Th2 paradigm of secreted cytokines after infection and how it play a roles in protection and pathogenesis for vaccine development and therapeutic interventions. Generally Th1 responses function to drive cell-‐mediated immunity whilst the Th2 responses influence the IgM to IgG and IgE antibody-‐mediated response.
The present study was not without its limitations and though each MAPK (JNK and p38) has a role and can influence several events including the transcriptional program within the cell after infection. The effect observed in the efficiency of viral replication and the levels and types of cytokines secreted in response to the infection, suggests collectively the contribution of type differences and other factors influence the overall outcome of the infection. It is plausible that the effects of factors influenced by the pathway are being inhibited by the IE and E viral pro-‐ teins that alternate downstream targets of p38 and JNK for efficient replication are being af-‐ fected; that the importance of the transcription factors upregulated in a cell-‐type and time-‐ dependent manner are masked by the culture system used and that the MAPK network, which is known like other pathways to have areas of cross-‐talk coupled with redundancy for regula-‐ tion, is robust enough to mask the true effect of inhibition of a select arm of the pathway. Also, though each inhibitor has specificty regarding their mechanism of action, care must be taken as research has shown that p38 inhibitors can activate or influence the levels of activated JNK and as such care must be taken in extrapolating information from inhibition the studies. However, with the development of peptide based inhibitors and allosteric modifiers of activated p38 and JNK (rather than ATP competitors) one may be able to not only have better targeting in inhibi-‐ tion but also increase efficacy.
7.5 Potential benefit of the investigated events
Virus infection leads to defined responses that are host-‐dependent and cell-‐type-‐ dependent. The infection leads to numerous manipulations within cells such that mRNA, pro-‐ teins, metabolites, channel activity and potentials as well as cell scaffold structures and mem-‐ branes are changed. All of theses changes can be characterized as a molecular signature. The
changes are a biochemical signature of the infection and they will have certain alterations that are restricted to the pathogen in a stated cell type. By investigating these signatures and dis-‐ secting the role of the pathways involved, we will not only be able to develop technology that can decipher what pathogen a cell type or person has come into contact with (diagnostic appli-‐ cation) but also be able to define types of proteins involved in specific biochemical changes that are either beneficial for the virus or lead to detrimental effects within the host.
Also this work highlights the importance of MAPK signaling post infection and the host dependent role factors regulated by the MAPK have in B virus infection. More importantly, the observed influence of inhibition on relative increases in proinflammatory cytokines IL6 and IL8, again suggests that the MAPK p38 and JNK may either directly or indirectly influence cytokine secretion and progression towards apoptosis in host cells. The observed p38 dampening of the replication in the natural host, and reduction of infectious virus in the foreign host after p38 inhibition points to a novel area not previously considered for therapeutics to B virus infection to be investigated. The propagation of signals that lead to a TH1 or a TH2 mediated response early after infection, can be a means for host survival and though we generally associate TH1 responses with antiviral clearance early after infection, it may be that the host survival is de-‐ pendant on the TH1 and TH2 balance such that the monkey (as shown in the data) is able to express factors associated with both responses and as such has cellular immunity and humoral immunity to control/limit the infection and spread of B virus.
The overall induction of MAPKs and role of MAPKs in B virus infection has been shown in this study to occur in a host dependent manner, and though not all induced events are virus
specific, the study highlighted the importance of MAPK’s in virus replication and cytokine secre-‐ tion, as summarized in Figure 6.48. This regulation and modulation involves a constant shift in the balance of transcription factors and cytokines such that their net effect is dependant on the time of release, the location of the effect, the responsiveness of cell within the area of the in-‐ fection, the density of receptors for the region of its effect and the overall composition of other competing or synergistic cytokines within the defined area. As such, future studies to address each of theses areas and how the interaction of primary fibroblast cells with other circulating cells found in the area post infection to limit replication and spread will assist in dissecting the overall mechanism by which the natural host is able to control the infection and survive.